Substituted benzoylbenzene-, biphenyl- and 2-oxazole-alkanoic acid derivatives as inhibitors of pla2 and lipoxygenase

ABSTRACT

There are disclosed compounds of the formula 
     
         A(CH.sub.2).sub.n O--B 
    
     wherein 
     A is a group having the formula ##STR1##  wherein X is --N-- or ##STR2## Z is ##STR3## R 1  is hydrogen, lower alkyl or phenyl; R 2  is hydrogen or lower alkyl; or 
     R 1  and R 2  taken together form a benzene ring, with the proviso that when X is --N--, Z is other than ##STR4## R 3  is hydrogen or lower alkyl; n is 1-2; 
     B is ##STR5##  wherein Y is OR 5  or N(OH)R 8  ; 
     R 4  and R 5  are each, independently, hydrogen or lower alkyl; 
     R 6  is hydrogen, halo or nitro; 
     R 7  is ##STR6## R 8  is lower alkyl; m is 0-3; 
     and the pharmacologically acceptable salts thereof, and their use in the treatment of inflammatory conditions, such as rheumatoid arthritis, ulcerative colitis, psoriasis and other immediate hypersensitivity reactions; in the treatment of leukotriene-mediated naso-bronchial obstructive air-passageway conditions, such as allergic rhinitis, allergic bronchial asthma and the like; and as gastric cytoprotective agents.

This is a continuation-in-part of U.S. Ser. No. 07/661,733, filed Feb.27, 1991 now abandoned, which is a continuation-in-part of U.S. Ser. No.07/427,677, filed Oct. 27, 1989, now abandoned.

This invention relates to novel substituted benzoylbenzene-,biphenyl-and 2-oxazole- alkanoic acid derivatives possessinglipoxygenase inhibitory, phospholipase A₂ inhibitory and leukotrieneantagonist activity, which are useful as anti-inflammatory, antiallergicand cytoprotective agents.

It is now well-established that arachidonic acid (AA) is metabolized inmammals by two distinct pathways. The metabolism of arachidonic acid bycyclooxygenase enzymes results in the production of prostaglandins andthromboxanes. The physiological activity of the prostaglandins hasalready been amply elucidated in recent years. It is now known thatprostaglandins arise from the endoperoxides PGG₂ and PGH₂ by thecyclooxygenase pathway of arachidonic acid metabolism. Theseendoperoxides are also the precursors of the thromboxanes (Tx) A₂ andB₂. TxA₂ is a vasoconstrictor which stimulates platelet aggregation. Inthe normal situation, the vasoconstrictive and platelet aggregatingproperties of the thromboxanes are balanced by another product arisingfrom the endoperoxides in the cyclooxygenase pathway, prostacyclin(PGI₂), which is a vasodilator with platelet aggregation inhibitoryactivity. In the event prostacyclin synthesis is impaired and/orplatelet activation is enhanced, then thrombosis and vasoconstriction isfavored. The role of prostanoids in haemostasis and thrombosis arereviewed by R. J. Gryglewski, CRC Crit. Rev. Biochem., 7, 291 (1980) andJ. B. Smith, Am. J. Pathol., 99, 743 (1980). Cyclooxygenase metabolitesare known to participate directly in the inflammatory response [seeHiggs et al., Annals of Clinical Research, 16, 287-299 (1984)]. This isthrough their vasodepressor activities, participation in pain and feveraugmentation of peptide mediator vascular permeability and edema formingproperties. Finally, various aspects of cell mediated immunity areinfluenced by cyclooxygenase products.

The other pathway of AA metabolism involves lipoxygenase enzymes andresults in the production of a number of oxidative products calledleukotrienes. The latter are designated by the LT nomenclature system,and the most significant products of the lipoxygenase metabolic pathwayare the leukotrienes B₄, C₄ and D₄. The substance denominatedslow-reacting substance of anaphylaxis (SRS-A) has been shown to consistof a mixture of leukotrienes, with LTC₄ and LTD₄ as the primary productsand having varying amounts of other leukotriene metabolites [see Bach etal., J. Immun., 215, 115-118 (1980); Biochem. Biophys. Res. Commun., 93,1121-1126 (1980)].

The significance of these leukotrienes is that a great deal of evidencehas been accumulated showing that leukotrienes participate ininflammatory reactions, exhibit chemotactic activities, stimulatelysosomal enzyme release and act as important factors in the immediatehypersensitivity reaction. It has been shown that LTC₄ and LTD₄ arepotent bronchoconstrictors of the human bronchi [see Dahlen et al.,Nature, 288, 484-486 (1980) and Piper, Int. Arch. Appl. Immunol., 76,suppl. 1, 43 (1985)] which stimulate the release of mucus from airwaysin vitro [Marom et al., Am. Rev. Resp. Dis., 126, 449 (1982)], arepotent vasodilators in skin [see Bisgaard et al., Prostaglandins, 23,797 (1982)], and produce a wheal and flare response [Camp et al., Br. J.Pharmacol., 80, 497 (1983)]. The nonpeptide leukotriene, LTB₄, is apowerful chemotactic factor for leukocytes [see A. W. Ford-Hutchinson,J. Roy. Soc. Med., 74, 831-833 (1981), which stimulates cellaccumulation and affects vascular smooth muscle [see Bray, Br. Med.Bull., 39, 249 (1983)]. The activity of leukotrienes as mediators ofinflammation and hypersensitivity is extensively reviewed in Bailey andCasey, Ann. Reports Med. Chem., 19, 87 (1986).

Phospholipase A₂ (PLA₂) is the critical rate limiting enzyme in thearachidonic acid (AA) cascade since it is responsible for the hydrolysisof esterified AA from the C-2 position of membrane phospholipids. Thisreaction generates two products (1) free AA which is then available forsubsequent metabolism by either the cyclooxygenase or lipoxygenaseenzymes and (2) lysophospholipid. Whenalkylarachidonoyl-glycerophosphatidylcholine is acted upon by the PLA₂the generation of platelet activating factor (PAF) is initiated; PAF ispro-inflammatory in its own right [see Wedmore et al., Br. J.Pharmacol., 74, 916-917 (1981)]. In this regard it may be noted that theanti-inflammatory steroids are thought to inhibit eicosanoid synthesisby inducing the synthesis of a PLA₂ inhibitory protein denominatedmacrocortin or lipomodulin [see Flower et al., Nature, London, 278, 456(1979) and Hirata et al., Proc. Natn. Acad. Sci. U.S.A., 77, 2533(1980)].

As the initial step leading to subsequent conversion of AA to thevarious eicosanoids by the cyclooxygenase and lipoxygenase pathways, thePLA₂ -mediated release of AA from membrane phospholipids is a criticalevent in attempting to deal with the various physiologicalmanifestations which are based on the activity of the eicosanoids and/orPAF. Thus, while PLA₂ has been shown to be required for plateletaggregation [Pickett et al., Biochem. J., 160, 405 (1976)], cardiaccontraction and excitation [Geisler et al., Pharm. Res. Commun., 9, 117(1977)], as well as prostaglandin synthesis [Vogt, Adv. Prostagl.Thromb. Res., 3, 89 (1978)], the inhibition of PLA₂ is indicated in thetherapeutic treatment of both PAF induced or cyclooxygenase and/orlipoxygenase pathway product-mediated physiological conditions.

There is also evidence that products of the cyclooxygenase/lipoxygenasepathways play key roles in both the pathogenesis of gastric mucosaldamage due to extracellular (gastric and intestinal contents,microorganisms, and the like) or intracellular (ischemia, viruses, etc.)agents, as well as in cytoprotection against such damage. Thus, on theone hand prostaglandins exert a cytoprotective effect on the gastricmucosa [see Robert, Gastroenterology, 77, 761-767 (1979)] and thisaction of the prostaglandins, especially of the E series, is consideredto be of importance in the treatment of gastro-intestinal ulceration[see Isselbacher, Drugs, 33 (suppl.), 38-46 (1987)]. On the other hand,ex vivo experiments have shown that gastric mucosal tissue fromethanol-pretreated rats is capable of LTC₄ generation and that this LTC₄production is quantitatively related to the severity of the ethanoldamage [see Lange et al., Naunyn-Schmiedeberg's Arch. Pharmacol. Suppl.,330, R27, (1985)]. It has also been demonstrated that LTC₄ can inducevasoconstriction in both venous and arteriolar vessels in the ratsubmucosa [see Whittle, IUPHAR Ninth Int. Cong. of Pharm., S30-2,London, England (1984)]. This is significant since ethanol-inducedlesion formation in gastric mucosa may be multifactorial with, forexample, stasis of gastric blood flow contributing significantly to thedevelopment of the hemorrhagic necrotic aspects of the tissue injury[see Guth et al., Gastroenterology, 87, 1083-90 (1984)]. Moreover, inthe anesthetized cat, exogenous LTD₄ evokes both increased pepsinsecretion and decreased transgastric potential [Pendleton et al., Eur.J. Pharmacol., 125, 297-99 (1986)]. A particularly significant recentfinding in this regard is that 5-lipoxygenase inhibitors and someleukotriene antagonists protect the gastric mucosa against lesionsinduced by the oral or parenteral administration of most nonsteroidalanti-inflammatory drugs [see Rainsford, Agents and Actions, 21, 316-319(1987)]. Platelet activating factor (PAF) is also implicated as amediator of gastrointestinal damage, and it has been recently shown that5-lipoxygenase inhibitors inhibit PAF-induced gastric mucosal damage(Gastroenterology, 96, A55, A434, 1989). Accordingly, a significant bodyof evidence implicates the involvement of lipoxygenase products in thedevelopment of pathological features associated with gastric mucosallesions, such as for example, those induced by ethanol exposure andadministration of non-steroidal anti-inflammatory drugs. Thus, compoundswhich inhibit the biological effects of leukotrienes and PAF and/orwhich control the biosynthesis of these substances, as by inhibiting5-lipoxygenase, are considered to be of value as cytoprotective agents.

Accordingly, the biological activity of the leukotrienes and SRS's, andof lipoxygenase as the enzyme leading to the metabolism of AA toleukotrienes, indicates that a rational approach to drug therapy toprevent, remove or ameliorate the symptoms of allergies, anaphylaxis,asthma and inflammation and for gastric cytoprotection must focus oneither blocking the release of mediators of these conditions orantagonizing their effects. Thus, compounds which inhibit the biologicaleffects of the leukotrienes and SRS's and/or which control thebiosynthesis of these substances, as by inhibiting the PLA₂ -mediatedrelease of arachidonic acid from membrane phospholipids, or byinhibiting lipoxygenase, are considered to be of value in treating suchconditions as allergic bronchial asthma, allergic rhinitis, as well asin other immediate hypersensitivity reactions and in providing gastriccytoprotection.

It has now been found that certain novel substituted benzoylbenzene-,biphenyl- and 2-oxazole- alkanoic acid derivatives inhibit PLA₂ andlipoxygenase, and antagonize products of the lipoxygenase pathway, andso are useful as anti-inflammatory, anti-allergic and cytoprotectiveagents. The present invention provides novel compounds having thefollowing formula:

    A(CH.sub.2).sub.n O--B

wherein

A is a group having the formula ##STR7## wherein X is --N-- or ##STR8##Z is ##STR9## R¹ is hydrogen, lower alkyl or phenyl; R² is hydrogen orlower alkyl; or

R¹ and R² taken together form a benzene ring, with the proviso that whenX is --N--, Z is other than ##STR10## R³ is hydrogen or lower alkyl; nis 1-2;

B is ##STR11## wherein Y is OR⁵ or N(OH)R⁸ ;

R⁴ and R⁵ are each, independently, hydrogen or lower alkyl;

R⁶ is hydrogen, halo or nitro;

R⁷ is ##STR12## R⁸ is lower alkyl; m is 0-3;

and the pharmacologically acceptable salts thereof.

The term "lower alkyl" refers to moieties having 1-6 carbon atoms in thecarbon chain. The term "halo" refers to fluoro, chloro or bromo.

The grouping A embraces, inter alia, 5- or 6-membered unsaturatednitrogen, sulfur or oxygen containing mono- or benzofused-heterocycles,optionally substituted with lower alkyl or phenyl. The foregoingdefinition embraces the following heterocyclic moieties: furyl,pyrrolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrazinyl,pyrimidinyl, benzofuranyl, benzothienyl, benzothiazolyl, indolyl,benzoxazolyl, quinazolinyl, benzimidazolyl, quinoxalinyl, quinazolinyland the like. Especially preferred are thiazolyl, benzothiazolyl,benzoxazolyl and benzimidazolyl.

The compounds of the invention can form pharmacologically acceptablesalts from pharmacologically acceptable organic and inorganic acids suchas hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitric,maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic,acetic, propionic, tartaric, citric, lactic, malic, mandelic, cinnamic,palmitic, itaconic and benzenesulfonic. The compounds which arecarboxylic acids are capable of forming alkali metal and alkaline earthcarboxylates and carboxylates of pharmacologically acceptable cationsderived from ammonia or a basic amine. Examples of the latter includebut are not limited to cations such as ammonium, mono-, di-, andtrimethylammonium, mono-, di- and triethylammonium, mono-, di- andtripropylammonium (iso and normal), ethyldimethylammonium,benzyldimethylammonium, cyclohexylammonium, benzylammonium,dibenzylammonium, piperidinium, morpholinium, pyrrolidinium,piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium,1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium,1-n-butyl-piperidinium, 2-methylpiperidinium,1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium, ethyldiethanolammonium, n-butylmonoethanolammonium,tris(hydroxymethyl)methylammonium, phenylmonoethanolammonium, and thelike.

The compounds of the invention can be prepared by the following reactionschemes. When it is desired to prepare compounds having the formula##STR13## 4-methoxybenzonitrile, for example, is reacted with3-bromotoluene, followed by reaction with bromine in ethylene bromide toyield the intermediate 3-bromomethyl-[4'-methoxy]benzophenone. ##STR14##The bromo intermediate is reacted with sodium cyanide to yield the cyanointermediate, which is hydrolyzed in the presence of base to yield thecarboxylic acid, which in turn is demethylated to yield the hydroxycarboxylic acid intermediate: ##STR15## The hydroxy carboxylic acidintermediate is converted to the methyl ester with methanol in thepresence of p-toluenesulfonic acid followed by reaction with anappropriate haloalkyl-A compound, where A is as defined hereinbefore andhal is halo, to yield the desired final product as the methyl ester.##STR16## The ester can be hydrolyzed by conventional methods to yieldthe desired final product in free carboxylic acid form.

Compounds having the formula ##STR17## can be prepared by reacting thefree carboxylic acid, whose preparation has been described above, withan appropriate N-alkylhydroxylamine in the presence ofcarbonyldiimidazole ##STR18##

Compounds of the invention having the formula ##STR19## can be preparedby several routes. Compounds in which R⁶ is nitro and R⁷ is the##STR20## moiety can be prepared as follows; for example:4-bromo-3-nitroacetophenone is reacted with 4-iodoanisole in thepresence of copper bronze, to yield the intermediate methoxy-containingbiphenyl, which is demethylated with aluminum bromide to yield thehydroxy intermediate. The latter is then reacted with an appropriatehaloalkyl-A compound, where A is as defined hereinbefore and hal ishalo, to yield the desired final product. ##STR21## Compounds in whichR⁶ is halo and R⁷ is the --CHCOOR⁵ moiety can be prepared by a processwhich utilizes the 4-methoxy-biphenyl intermediate of the precedingscheme. Thus, the 4-acetyl-4-methoxy-2-nitrobiphenyl intermediate of theprevious scheme is subjected to reduction with stannous chloride toyield the intermediate amino derivative, which is then subjected toreplacement of the amino group with a halo group. For example, the aminogroup can be replaced with fluorine via a diazonium fluoroboratetransitory intermediate prepared from the amino intermediate usingsodium nitrite and tetrafluoroboric acid. The resultingacetyl-fluoro-methoxy biphenyl intermediate is converted to thecorresponding carboxylic acid followed by demethylation with hydrogenbromide to yield the 2-fluoro-4'-hydroxy-[1,1'-biphenyl]-4-acetic acidintermediate: ##STR22## The latter carboxylic acid intermediate isesterified with methanol in the presence of p-toluenesulfonic acid andthe latter is reacted with an appropriate haloalkyl-A compound, where Ais as defined hereinbefore and hal is halo, to yield the desired finalproduct as the methyl ester. ##STR23## The ester can be hydrolyzed byconventional methods to yield the desired final product in its freecarboxylic acid form.

Compounds in which R⁷ is one of the nitrogen-containing moieties can beprepared from the carboxylic acid form of the above-discussed finalproducts. Several possible sequences for these preparations are outlinedbelow: ##STR24##

Compounds in which R⁷ represents a reverse hydroxamic acid or urea canbe prepared according to the following scheme ##STR25##

Compounds of the invention having the formula ##STR26## can be preparedas follows. Benzaldehyde and 4-methoxybenzaldehyde are reacted to yield4-methoxybenzoin, which is converted to the hemisuccinate by reactionwith succinic anhydride. The latter is reacted with urea and acetic acidto yield the intermediate4-(4-methoxyphenyl)-5-phenyl-2-oxazole-propionic acid. ##STR27## Thelatter intermediate is demethylated with hydrogen bromide and esterifiedwith methanol to yield the corresponding hydroxy methyl esterintermediate, which is then reacted with an appropriate haloalkyl-Acompound, where A is as defined hereinbefore and hal is halo, to yieldthe desired final product as the methyl ester. ##STR28## The ester canbe hydrolyzed by conventional methods to yield the desired final productin its free carboxylic acid form.

Compounds of the invention having the formula ##STR29## can be preparedfrom the carboxylic acid form of the above-discussed final products.Thus, the free acid is reacted with an appropriate N-alkylhydroxylaminein the presence of carbonyldiimidazole: ##STR30##

The conventional starting materials used in the reaction sequencesoutlined above are available commercially or can be prepared by methodsknown in the art. Thus, for example, the intermediate compound2-bromomethylquinoline can be prepared by the following reactionsequence: ##STR31## The benzo-fused heterocyclic compounds used in theabove reaction sequences are also either commercially available or canbe prepared by methods conventional in the art. Thus, for example, suchintermediates as 1-methyl-2-chloromethylbenzimidazole,2-chloromethylbenzthiazole and 2-chloromethylbenzoxazole can be preparedby the following reaction scheme ##STR32## wherein X is O, S or NCH₃.The reaction is preferably carried out at a controlled low temperaturein an organic solvent, such as methylene chloride.

The compounds of the invention, by virtue of their ability to inhibitthe activity of PLA₂ enzyme, as well as that of lipoxygenase enzyme andto antagonize mediators arising from the enzymatic pathway, are usefulin the treatment of conditions mediated by products of the oxidation ofarachidonic acid. Accordingly, the compounds are indicated in thetreatment of such diseases as rheumatoid arthritis, inflammatory boweldisease, osteoarthritis, tendinitis, bursitis, psoriasis (and relatedskin inflammation) and similar conditions involving inflammation.Moreover, by virtue of their ability to antagonize the effect of LTC₄,LTD₄ and LTE₄, which are the constituents of SRS-A, they are useful forthe inhibition of symptoms induced by these leukotrienes. Accordingly,the compounds are indicated in the prevention and treatment of thosedisease states in which LTC₄, LTD₄ and LTE₄ are causative factors, forexample allergic rhinitis, allergic bronchial asthma and otherleukotriene mediated nasobronchial obstructive air-passagewayconditions, as well as in other immediate hypersensitivity reactions,such as allergic conjunctivitis. The compounds are especially valuablein the prevention and treatment of allergic bronchial asthma.

The compounds of the invention are cytoprotective agents and areconsidered especially useful when administered with conventionalnon-steroidal anti-inflammatory drugs, whose major side effect isgastrointestinal irritation. The cytoprotective effect of the compoundsof the invention significantly reduces the gastroirritant impact ofconventional anti-inflammatory drugs. This effect is based not only onthe ability of the compounds of the invention to inhibit the biologicaleffects of leukotrienes and/or control the biosynthesis of thesesubstances, as by inhibiting lipoxygenase, but also by a shuntingeffect, whereby the control of the lipoxygenase pathway "shunts" theoxidation of arachidonic acid into the cyclooxygenase pathway, givingrise to an increase in the formation of cytoprotective prostaglandins.These biological effects make the compounds of the invention especiallyuseful in treating such conditions as erosive esophagitis, inflammatorybowel disease and induced hemorrhagic lesions such as those induced byalcohol or non-steroidal anti-inflammatory drugs (NSAID's), hepaticischemia, noxious agent induced damage or necrosis of hepatic,pancreatic, renal or myocardial tissue; liver parenchymal damage causedby hepatotoxic agents such as carbon tetrachloride and D-galactosamine;ischemic renal failure; disease-induced hepatic damage; bilesalt-induced pancreatic or gastric damage; trauma or stress-induced celldamage; and glycerol-induced renal failure.

When the compounds of the invention are employed in the treatment ofallergic airway disorders, as anti-inflammatory agents and/or ascytoprotective agents, they can be formulated into oral dosage formssuch as tablets, capsules and the like. The compounds can beadministered alone or by combining them with conventional carriers, suchas magnesium carbonate, magnesium stearate, talc, sugar, lactose,pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, low melting wax, cocoa butter and the like.Diluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, tablet-disintegrating agents and the like may be employed. Thecompounds may be encapsulated with or without other carriers. In allcases, the proportion of active ingredients in said compositions bothsolid and liquid will be at least to impart the desired activity theretoon oral administration. The compounds may also be injected parenterally,in which case they are used in the form of a sterile solution containingother solutes, for example, enough saline or glucose to make thesolution isotonic. For administration by inhalation or insufflation, thecompounds may be formulated into an aqueous or partially aqueoussolution, which can then be utilized in the form of an aerosol.

The dosage requirements vary with the particular compositions employed,the route of administration, the severity of the symptoms presented andthe particular subject being treated. Treatment will generally beinitiated with small dosages less than the optimum dose of the compound.Thereafter the dosage is increased until the optimum effect under thecircumstances is reached. In general, the compounds of the invention aremost desirably administered at a concentration that will generallyafford effective results without causing any harmful or deleterious sideeffects, and can be administered either as a single unit dose, or ifdesired, the dosage may be divided into convenient subunits administeredat suitable times throughout the day.

The PLA₂ and lipoxygenase inhibitory and leukotriene antagonist effects,as well as the anti-inflammatory and potential gastroirritant effects ofthe compounds of the invention, may be demonstrated by standardpharmacological procedures which are described more full in the examplesgiven hereinafter.

These procedures, inter alia, determine the specificity of action of thecompounds of the invention as PLA₂ inhibitors as measured by theirability to inhibit the synthesis of LTB₄ and PGE₂ by ratglycogen-elicited polymorphonuclear leukocytes, as well as measure theirability to inhibit arachidonic acid release mediated by human sourcePLA₂. The pharmacological testing additionally demonstrates the abilityof the compounds of the invention to inhibit, in vivo, the lipoxygenaseand cyclooxygenase pathways of arachidonic acid metabolism; theirability to inhibit 5-lipoxygenase in human whole blood; their ability toantagonize LTD₄ -induced contractions of isolated guinea pig trachea;and their ability to inhibit LTB₄ biosynthesis by purified humanneutrophils.

The following examples show the preparation and pharmacological testingof compounds within the invention.

EXAMPLE 1 1-[2-Nitro-4'-(2-quinolinylmethoxy)-[1,1'-biphenyl]4-yl]ethanone

A. 4-Acetyl-4'-methoxy-2-nitro biphenyl

A stirred mixture of 4-iodoanisole (43.65 g, 0.187 mole),4-bromo-3-nitro acetophenone (40.6 g, 0.166 mole) and copper powder(copper bronze, 36 g, 0.567 mole) kept under nitrogen is placed in anoil bath heated at 80° C. The temperature is slowly raised to 110° C.and the mixture is kept at this temperature for 5 days (TLC, 8:2hexane-ethyl acetate). Upon cooling the mixture is dissolved indichloromethane and filtered through a Celite pad. The filtrate andwashing are evaporated and the residual thick, dark brown oil (58.4 g)is flash chromatographed (on silica Merck 60, preabsorbed indichloromethane, eluted with 9:1 hexane-ethyl acetate to remove theimpurities and 8:2 hexane-ethyl acetate to recover the main product) toprovide 16.2 g (32%) of the title compound (yellow solid, m.p.124°-126°C.).

NMR (CDCl₃, 400 MHz): δ2.67 (s,3H, COCH₃), 3.85 (s, 3H, OCH₃), 6.97 (d,2H, J 8.74 Hz, ArH), 7.27 (d, 2H, J 8.74 Hz, ArH), 7.56 (d, 1H, J 8 Hz,ArH), 8.15 (d, 1 H, J 8 Hz, ArH), 8.34 (s, 1H, ArH)

MS (EI, m/z): 271 (M)⁺.

B. 4-Acetyl-4'-hydroxy-2-nitro biphenyl

To a stirred solution of AlBr₃ (12.6 g, 47.4 mmole) in benzene (45 mL)is added dropwise under nitrogen a solution of the methylether (5 g,18.45 mmole) of Step A in benzene (12 mL) over 30 minutes. The resultingsolution is stirred at room temperature for 3.5 hours. (TLC, 8:2hexane-ethyl acetate). The mixture is cooled in an ice bath and thecomplex is decomposed by the dropwise addition of 6N-HCl (ca. 37 mL).The organic layer is separated and the aqueous phase is reextracted withether (3×). The combined extracts are concentrated to a small volume andextracted again with 2.5N-NaOH (2×50 mL +1×10 mL). The basic extractsare cooled and acidified with concentrated HCl (to pH 2). The solid iscollected and dried (4.27 g, 90%). It is used in the next step withoutfurther purification.

NMR (CDCl₃, 400 MHz): δ2.67 (s, 3H, COCH₃), 5.03 (broad, 1H, OH), 6.91(d, 2H, J 8.56 Hz, ArH), 7.23 (d, 2H, J 8.57 Hz, ArH), 7.55 (d, 1H, J7.9 Hz, ArH), 8.15 (d, 1H, J 8.1 Hz, ArH), 8.34 (s, 1H, ArH).

MS (EI, m/z): 257 (b.p.,M)⁺.

C. 1-[2-Nitro-4'-(2-quinolinyl)[1,1'-biphenyl-4-yl]ethanone

A mixture of the phenol (4.4 g, 17.12 mmole) of Step B, powderedanhydrous potassium carbonate (2.37 g, 17.12 mmole), 18-crown-6 (0.453g, 1.71 mmole) and acetonitrile (38 mL) is stirred at room temperatureunder nitrogen for 15 minutes. 2-Chloromethylquinoline (3.34 g, 18.83mmole, free base freshly prepared from the hydrochloride salt) is addedand the mixture is refluxed for 10 hours. (TLC, 7:3 hexane-ethylacetate). A 10% excess of potassium carbonate, 18-crown-6 and thechloromethylquinoline is added and reflux continued for another 4 hours.The solvent is removed and the residue is diluted with water andextracted with ethyl acetate (3×). The extracts are washed and dried(MgSO₄). The residue is flash chromatographed (on silica Merck 60,preabsorbed in dichloromethane and eluted in order of increasingpolarity with 7:3, 1:1 and 1:3 hexane-ethyl acetate followed by pureethyl acetate) to provide the pure title compound (2.59 g).Recrystallization from toluene yields a yellow solid, m.p. 160°-162° C.(2.05 g, 30%).

NMR (CDCl₃, 400 MHz): δ2.66 (s, 3H, COCH₃), 5.43 (s, 2H, OCH₂ Ar), 7.10(d, 2H, J 8.7 Hz, ArH), 7.27 (d, 2H, J 8.7 Hz, ArH), 7.56 (m, 2H, ArH),7.68 (d, 1H, J 8.49 Hz, ArH), 7.75 (dt, 1H, ArH), 7.84 (d, 1H, J 8.1 Hz,ArH), 8.09 (d, 1H, J 8.5 Hz, ArH), 8.14 (dd, 1H, ArH), 8.22 (d, 1H, J8.49 Hz, ArH), 8.34 (s, 1H, ArH).

MS (EI, m/z): 398 (M)⁺, 256,158,142 (b.p.).

Analysis for: C₂₄ H₁₈ N₂ O₄ : Calculated: C, 72.35; H, 4.55; N, 7.03.Found: C, 71.96; H, 4.75; N, 6.80.

EXAMPLE 2 2-Fluoro-4'-(2-quinolinylmethoxy)-[1,1'-biphenyl]-4-aceticacid

A. 4-Acetyl-4'-methoxy-2-amino biphenyl

To a stirred, warm solution of tin (II) chloride (49.4 g, 218.9 mmole)in a mixture of concentrated HCl (72 mL) and ethanol (99 mL) is addedover a period of 45 minutes the nitro derivative (10.7 g, 39.5 mmole) ofExample 1A. The resulting yellow solution is refluxed for 3.5 hours(TLC, 1:1 hexane-ethyl acetate). The ethanol is removed and the residueis poured into a mixture of 50% NaOH (360 mL) and ice. The resultingsolid is extracted (dichloromethane, 3×), the extracts are washed withwater and dried (Na₂ SO₄). Removal of the solvent provides a yellowsolid (9.31 g, 97.8%), m.p. 152°-154° C.

NMR (CDCl₃, 400 MHz): δ2.59 (s, 3H, COCH₃), 3.80 (s, 3H, OCH₃), 6.97 (d,2H, J 8.7 Hz, ArH), 7.23 (d, 1H, J 7.4 Hz, ArH), 7.40 (d, 2H, J 8.7 Hz,ArH), 7.48 (d, 1H, J 7.3 Hz, ArH), 7.49 (s, 1H, ArH).

MS (EI, m/z): 241 (b.p., M)⁺, 226 (M-CH₃)⁺, 198 (M-COCH₃)⁺, 83.

B. 4-Acetyl-4'-methoxy-2-fluoro biphenyl

To a stirred, ice cold mixture of the aniline (9.2 g, 38.2 mmole) intetrahydrofuran (26 mL), water (9.8 mL) and HBF₄ (48%, 35.1 mL) isslowly added a solution of sodium nitrite (2.82 g, 40.85 mmole) in water(5 mL). The internal temperature is kept below 5° C. during theaddition. The mixture is then stirred for an additional 20 minutes at0°-5° C. The diazonium fluoroborate is filtered off and washed with 10%HBF₄ and 10% methanol in ether and dried in vacuo. The salt isdecomposed by heating at 70° C. in xylene (95 mL). When thedecomposition subsides, the mixture is refluxed for another 2.5 hours(TLC, 1:1 hexane-ethyl acetate, UV). The xylene is removed and theresidue is extracted with ethyl acetate (3×) and ether. The combinedextracts are washed with 10% sodium carbonate and brine and dried(MgSO₄). Removal of the solvent provides an amber oil (6.03 g) which ispurified by flash chromatography (on silica Merck 60, preabsorbed indichloromethane and eluted with 95:5 hexane-ethyl acetate). The titlecompound is obtained as a yellow solid 3.12-4.75 g, (33-51% depending onthe run); m.p. 100°-101° C.

NMR (CDCl₃, 400 MHz): δ2.62 (s, 3H, COCH₃), 3.86 (s, 3H, OCH₃), 7.00 (d,2H, J 8.9 Hz, ArH), 7.50-7.80 (m, 5H, ArH).

MS (EI, m/z): 244 (M)⁺, 229 (b.p., M-CH3)⁺.

C. 2-Fluoro-4'-methoxy-[1,1'-biphenyl]-4-acetic acid

A mixture of sulfur (0.468 g, 14.6 mmole), morpholine (2.57 mL) and theketone (3.95 g, 16.2 mmole) of Step A is refluxed for 17 hours (TLC,acid treated silica plate, 8:2 hexane-ethyl acetate). Upon cooling,glacial acetic acid (9.9 mL), sulfuric acid (1.6 mL) and water (4 mL)are added and the reflux resumed for 30 hours. Water is then added andthe mixture is extracted with ether (3×). The combined extracts areconcentrated to a smaller volume and extracted with 10% sodiumcarbonate. The basic extracts are carefully acidified in the cold withconcentrated HCl (to pH 2). The title acid is extracted with ether (3×)and the extracts are washed and dried (MgSO₄). Removal of the solventprovides a tan to brown solid (2.37 g, 56.3%) melting at 140°-142° C.

NMR (CDCl₃, 400 MHz): δ3.68 (s, 2H, CH₂ COO), 3.85 (s, 3H, OCH₃),6.96-7.50 (m, 7H, ArH).

MS (EI, m/z): 260 (M)⁺, 215 (b.p., M-COOH)⁺.

D. 2-Fluoro-4'-hydroxy-[1,1'-biphenyl]-4-acetic acid

To a solution of the methylether (1.31 g, 5.04 mmole) of Step C inglacial acetic acid (17 mL) is added dropwise 48% HBr in acetic acid (25mL) and the mixture is refluxed for 4.5 hours (TLC, 7:3 hexane-ethylacetate). A little water is added and the mixture is extracted withether (3×). The extracts are washed and dried (MgSO₄). Removal of thesolvent provides the title compound as a tan solid (1.13 g, 92%), m.p.208°-210° C.

NMR (DMSO-d₆, 400 MHz): δ3.61 (s, 2H, CH₂ COO), 6.83 (d, 2H, J 8.64 Hz,ArH), 7.1-7.42 (m, 5H, ArH), 9.61 (s, 1H, COOH).

MS (CI, m/z): 246 (M)⁺, 201 (b.p., M-COOH)⁺.

E. 2-Fluoro-4'-hydroxy-[1,1'-biphenyl]-4-acetic acid methylester

A solution of the acid (1.1 g, 4.47 mmole) of Step D in methanol (10 mL)containing p-toluenesulfonic acid. H₂ O (0.159 g) is refluxed for 1.5hours (TLC, acid treated silica plate, hexane-ethyl acetate 7:3). Thesolvent is removed, the residue is dissolved in ethyl acetate, washedwith brine and dried (MgSO₄). The tan solid (1.16 g, m.p. 115°-118° C.,quantitative yield) is used as such in the next step.

NMR (CDCl₃, 400 MHz): δ3.65 (s, 2H, CH₂ COO), 3.73 (s, 3H, COOCH₃), 6.88(d, 2H, J 8.8 Hz, ArH), 7.10 (m, 2H, ArH), 7.32-7.44 (m, 3H, ArH).

MS (EI, m/z): 260 (M)⁺, 201 (b.p., M-COOCH₃)⁺.

F. 2-Fluoro-4'-(2-quinolinylmethoxy)-[1,1'-biphenyl]-4-acetic acidmethylester

A stirred mixture of the phenol (1.16 g, 4.46 mmole) of Step E, powderedanhydrous potassium carbonate (0.616 g, 4.46 mmole), 18-crown-6 (0.118g, 0.445 mmole) and acetonitrile (10 mL) is stirred at room temperatureunder nitrogen for 15 minutes. 2-Chloromethylquinoline (0.871 g, 4.9mmole, free base freshly prepared from the hydrochloride salt) is thenadded and the mixture is placed in an oil bath heated at 65° C. for 5hours. A 10% excess of potassium carbonate, 18-crown-6 and thechloromethylquinoline is added and the heating continued for another 6hours (TLC, 19:1 dichloromethane-methanol or 7:3 hexane-ethyl acetate).The solvent is removed and the residue is diluted with water andextracted with ethyl acetate (3×). The extracts are washed and dried(MgSO₄). Removal of the solvent provides a tan solid which is purifiedby flash chromatography (on silica Merck 60, preabsorbed withdichloromethane, eluted with 7:3 hexane-ethyl acetate). The titlecompound thus obtained (1.55 g, 87%) is recrystallized from methanol.The off-white solid melts at 99°-101° C.

NMR (CDCl₃, 400 MHz): δ3.64 (s, 2H, CH₂ COO), 3.72 (s, 3H, COOCH₃), 5.43(s, 2H, OCH₂ Ar), 7.1 (m, 4H, ArH), 7.35 (t, 1H, ArH), 7.47 (d, 2H,ArH), 7.55 (t, 1H, ArH), 7.69 (d, 1H, ArH), 7.74 (t, 1H, ArH), 7.84 (d,1H, ArH), 8.09 (d, 1H, ArH), 8.20 (d, 1H, ArH).

MS (EI, m/z): 401 (M)⁺, 142, 114 (b.p.).

Analysis for: C₂₅ H₂₀ FNO₃ : Calculated: C, 74.80; H, 5.02; N, 3.49.Found: C, 74.68; H, 4.65; N, 3.49.

G. 2-Fluoro-4'-(2-quinolinylmethoxy)-[1,1'-biphenyl]-4-acetic acid

A solution of the ester (1.69 g, 4.21 mmole) of Step F, in drytetrahydrofuran (20 mL) is treated dropwise under nitrogen with 1N-LiOH(12.6 mL) and the mixture is stirred for 3 hours at room temperature(TLC, 19:1 dichloromethane-methanol or 1:1 hexane-ethyl acetate). Thesolvent is removed, the residue is treated with water and neutralized(to pH 6.5) with 10% acetic acid. The acid is extracted with ethylacetate (large volume needed) and the extracts are dried (MgSO₄) andevaporated to dryness to yield an off-white solid (1.65 g, quantitativeyield, m.p. 190°-193° C., dec.). Recrystallization from ethyl acetateprovides a white solid (1.32 g, 80%, m.p. 195°-196° C. dec.). Theanalytical sample is dried in vacuo at 40° C.

NMR (DMSO-d₆, 400 MHz): δ3.62 (s, 2H, CH₂ COO), 5.41 (s, 2H, CH₂ OAr),7.15 (m, 4H, ArH), 7.41 (t, 1H, J 8 Hz, ArH), 7.48 (d, 2H, ArH), 7.61(t, 1H, ArH), 7.69 (d, 1H, ArH), 7.78 (dt, 1H, ArH), 8.01 (m, 2H, ArH),8.42 (d, 1H, ArH), 12.42 (s, COOH).

MS (+FAB, m/z): 388 (M)⁺.

Analysis for: C₂₄ H₁₈ FNO₃ :

Calculated: C, 74.41; H, 4.68; N, 3.62.

Found: C, 74.28; H, 4.48; H, 3.69.

EXAMPLE 3 3-[4-(2-Quinolinylmethoxy)benzoyl]benzene acetic acid

A. 3-Methyl-[4'-methoxy]-benzophenone

A 3-neck flask equipped with a condenser, mechanical stirrer anddropping funnel is charged under nitrogen with 1.925 g (79.19 g.a.) ofmagnesium turnings and enough ether to cover the turnings. A few dropsof a solution of 3-bromotoluene (15.79 g, 92.28 mmole) in ether (40 mL)is then added along with a crystal of iodine to initiate the reaction.The remainder of the solution is then added dropwise and the mixture isrefluxed until most of the magnesium has disappeared. After cooling, asolution of 4-methoxybenzonitrile (10 g, 75.1 mmole, dried in vacuo overP₂ O₅) is added in one portion. The mixture is refluxed for 2 hours(TLC, no starting material present), cooled (ice bath) and slowlytreated with cold water (130 mL) followed by dilute H₂ SO₄ (1:1, v/v, 25mL). The decomposition of the complex is completed by refluxing themixture for 4 hours (followed by TLC, 8:2 ether-ethyl acetate).Following stirring overnight at room temperature, the layers areseparated and extracted with ether (3×). The extracts are washed with 5%NaHCO₃, dried (MgSO₄) and evaporated to dryness. The crude material(amber oil, 13.93 g) is purified by flash chromatography (on silicaMerck-60, eluted with 8:2 petrolether-ethyl acetate) to provide thetitle compound as a light yellow oil (12.5 g, 73.5%).

NMR (CDCl₃, 400 MHz): δ2.4 (s, 3H, CH₃), 3.9 (s, 3H, OCH₃), 6.96 (d, J8.8 Hz, 2H, ArH), 7.38 (m, 2H, ArH), 7.53 (d, J 6.9 Hz, 1H, ArH), 7.57(s, 1H, ArH), 7.82 (d, J 8.7 Hz, 2H, ArH).

MS (EI, m/z): 226 (M)⁺, 135 (b.p.), 91.

B. 3-Bromomethyl-[4'-methoxy]-benzophenone

A solution of the benzophenone (17.5 g, 77.4 mmole) of Step A inethylene bromide (26.5 mL) (containing a small amount of benzoylperoxide) is heated at reflux. A solution of bromine (12.7 g, 79.6mmole) in ethylene bromide (15 mL) is added dropwise over 30 minuteswhile the mixture is irradiated with a Photolamp (300 W). Reflux iscontinued for 17 hours (TLC, 9:1 petrolether-ethylacetate, traces ofstarting material still present). The solvent is removed in vacuo andthe residue (brown oil, 39.22 g) is purified by flash chromatography (onsilica Merck-60, preabsorbed in dichloromethane, eluted with 9:1petrolether-ethyl acetate) to give unreacted starting material (2.59 g,ca. 15%) along with the desired product (14.36 g, 61% or 71.5% based onrecovered unreacted starting material) and some mixed fraction (ca. 5.20g). The light yellow solid melts at 58°-61° C. and it is used as such inthe next step.

NMR (CDCl₃, 400 MHz): δ3.88 (s, 3H, OCH₃), 4.52 (s, 2H, CH₂ Br), 6.96(d, J 8.8 Hz, 2H, ArH) 7.44 (t, J 7.6 Hz, 1H, ArH), 7.58 (d, J 7.8 Hz,1H, ArH), 7.66 (d, J 7.6 Hz, 1H, ArH), 7.76 (s, 1H, ArH), 7.81 (d, J 8.8Hz, 1H, ArH).

MS (EI, m/z): 306/304 (1 bromine, M)⁺, 225, 135 (b.p.). Trace of dibromoat 386/384/382 (possibly ##STR33##

C. 3-Cyanomethyl-[4'-methoxy]-benzophenone

The bromo compound (14 g, 45.9 mmole) of Step B, is dissolved in dioxane(30 mL) and a solution of NaCN (7 g) in water (28.5 mL) is added. Themixture is refluxed for 6 hours (TLC, petrolether-ethyl acetate 8:2),charcoalized if needed and extracted with ether (3×). The extracts aredried (MgSO₄) and evaporated to dryness to yield a brown oil (13.44 g).The crude product is purified by flash chromatography (on silicaMerck-60, preabsorbed in dichloromethane, eluted with 6:4 hexane-ethylacetate) to provide the pure product (10.69 g, 92%) as a light yellowoil that sets up upon standing. The nearly colorless solid melts at70°-71° C.

NMR (CDCl₃, 400 MHz): δ3.80 (s, 2H, CH₂ CN), 3.87 (s, 3H, OCH₃), 6.95(d, J 8.6 Hz, 2H, ArH), 7.48 (t, J 7.7 Hz, 1H, ArH), 7.54 (d, J 7.6 Hz,1H, ArH), 7.68 (s+d, J 7.6 Hz, 2H, ArH), 7.79 (d, J 8.6 Hz, 2H, ArH).

MS (EI, m/z): 251 (M)⁺, 135 (b.p.).

D. 3-[4-Methoxybenzoyl]-phenylacetic acid

The nitrile (4 g, 15.9 mmole) of Step C, is dissolved in 40% NaOH (40mL) and the solution is heated at reflux under nitrogen for 7 hours(TLC, toluene-methanol 9:1). Water is added while cooling in an icebath. The solution is washed with ethyl acetate and then acidified inthe cold with concentrated HCl (to pH 2). The acid is extracted withethyl acetate (3×) and the extracts are dried (MgSO₄) and evaporated todryness to yield the crude product (yellow solid, 3.56 g, 82%), m.p.138°-140° C.

NMR (CDCl₃, 400 MHz): δ3.72 (s, 2H, CH₂ COO), 3.88 (s, 3H, OCH₃), 6.95(d, J 8.8 Hz, 2H, ArH), 7.43 (t, 1H, ArH), 7.48 (d, 1H, ArH), 7.65 (d,1H, ArH), 7.68 (s, 1H, ArH), 7.81 (d, J 8.6 Hz, 2H, ArH).

MS (EI, m/z): 270 (M)⁺, 211 (M-CH₂ COOH)⁺, 135 (b.p.), 107.

E. 3-[4-Hydroxybenzoyl]-phenylacetic acid

An intimate mixture of the acid (8.1 g, 0.030 mole) of Step D, andpyridine hydrochloride (13.87 g, 0.120 mole) is stirred under nitrogenin an oil bath heated at 200°-210° C. for 7 hours (TLC, toluene-methanol9:1, dichloromethane-methanol 9:1). After cooling, the mixture isdissolved in dichloromethane. The solution is extracted with 1N-NaOH,the extract acidified in the cold with concentrated HCl and extractedwith ethyl acetate (3×). After drying (MgSO₄) the solvent is removed toprovide the crude title compound as a tan solid (7.61 g, quantitativeyield), m.p. 147°-149° C.

NMR (DMSO-d₆, 400 MHz): δ3.67 (s, 2H, CH₂ COO), 6.88 (d, J 8.84 Hz, 2H,ArH), ca. 7.5 (m, 4H, ArH), 7.65 (d, J 8.8 Hz, 2H, ArH), 10.4 (s, 1H,OH), ca. 12.3 (s, 1H, COOH).

MS (m/z): 257 (M+H)⁺, 217, 131, 91 (b.p.).

F. 3-[4-Hydroxybenzoyl]-phenylacetic acid methylester

A mixture of the acid (8.56 g, 33.4 mmole) of Step E andp-toluenesulfonic acid monohydrate (1.05 g, 5.6 mmole) in methanol (70mL) is refluxed for 2.5 hours (TLC, methanol-toluene 1:9). The methanolis evaporated and the residue is dissolved in ethyl acetate and washedwith brine. After drying (MgSO₄) the solvent is removed to yield a tansolid (8.68 g, 96.2%, m.p. 111°-113° C.). The crude product is used assuch in the next step.

NMR (CDCl₃, 400 MHz): δ3.69 (s, 2H, CH₂ COO), 3.69 (s, 3H, COOCH₃), 6.86(d, J 8.4 Hz, 2H, ArH), 7.41 (t, 1H, 7.58 Hz, 1H, ArH), 7.47 (d, J 7.56Hz, 1H, ArH), 7.62 (d, J 7.4 Hz, 1H, ArH), 7.64 (s, 1H, ArH), 7.74 (d,2H, J 8.4 Hz, ArH).

MS (m/z): 271(M+H)⁺, 217, 131, 91 (b.p.).

G. 3-[4-(2-Quinolinylmethoxy)benzoyl]benzene acetic acid methylester

A mixture of the phenol (4 g, 14.8 mmole) of Step F, powdered anhydrousK₂ CO₃ (2.05 g, 14.8 mmole) and 18-crown-6 (0.4 g, 1.48 mmole) inacetonitrile (35 mL) is stirred at room temperature under nitrogen for15 minutes. 2-Chloromethylquinoline (2.9 g, 16.28 mmole, freshlyprepared from the hydrochloride salt) is added in one portion and themixture is heated in an oil bath kept at 65°-70° C. for 8 hours (TLC,toluene-methanol 9:1). A 10% excess of K₂ CO₃, crown ether andchloromethylquinoline is added and the heating is continued for another8 hours. The acetonitrile is evaporated and the residue is partitionedbetween water and ethyl acetate. The organic layer is dried (MgSO₄) andevaporated to yield a tan solid (6.57 g). The crude product is purifiedby flash chromatography (on silica Merck-60, preabsorbed indichloromethane, eluted with petrolether-ethyl acetate 7:3) to give thetitle compound as a light yellow solid (5.03 g, 82.7%) m.p. 93°-95° C.

NMR (CDCl₃, 400 MHz): δ3.67 (s,5H, CH₂ COO +OCH₃), 5.45 (s, 2H, ArCH₂O), 7.08 (d, J 8.8 Hz, 2H, ArH), 7.40 (t, J 7.8 Hz, 1H, ArH), 7.46 (d, J7.7 Hz, 1H, ArH), 7.55 (t, J 7.3 Hz, 1H, ArH), 7.6-7.66 (m, 3H, ArH),7.7-7.82 (m, 4H, ArH), 8.07 (d, 1H, ArH), 8.20 (d, J 8.4 Hz, 1H, ArH).

MS (EI, m/z): 411 (M)⁺, 142, 121 (b.p.).

H. 3-[4-(2-Quinolinylmethoxy)benzoyl]benzene acetic acid

To a solution of the ester (5 g, 12.16 mmole) of Step G, in drytetrahydrofuran (66 mL) is added 1N-LiOH (37 mL, 37 mmole) and themixture is stirred under nitrogen at room temperature for 2.5 hours(TLC, toluene-MeOH 9:1). The tetrahydrofuran is evaporated and theresidue is diluted with water, acidified (to pH 6.5) with 10% aceticacid and extracted with ethyl acetate (3×). The extracts are washed withbrine, dried (MgSO₄) and evaporated to dryness. The crude product (4.94g, pale yellow solid) is recrystallized from ethyl acetate to provide3.65 g (75%) of the pure title compound (white solid, m.p. 146°-147°C.).

NMR (DMSO-d₆, 400 MHz): δ3.68 (s, 2H, CH₂ COO), 5.48 (s, 2H, ArCH₂ O),7.22 (d, 2H, J 8.8 Hz, ArH), 7.47 (m, 1H, ArH), 7.53 (m, 2H, ArH), 7.62(m, 2H, ArH), 7.69 (d, J 8.4 Hz, 1H, ArH) 7.74-7.82 (m, 3H, ArH), 8.2(m, 2H, ArH), 8.43 (d, J 8.5 Hz, 1H, ArH), 12.39 (1H, COOH).

MS (EI, m/z): 397 (b.p., M)⁺, 380 (M-OH)⁺, 142.

Analysis for: C₂₅ H₁₉ NO₄ Calculated: C, 75.57; H, 4.78; N, 3.53. Found:C, 75.22; H, 4.76; N, 3.39.

EXAMPLE 4 3-[4-(2-Naphthalenylmethoxy)benzoyl]benzene acetic acid

A. 3-[4-(2-Naphthalenylmethoxy)benzoyl]benzene acetic acid methylester

A mixture of the phenol (1 g, 3.7 mmole) of Example 3F, powderedanhhydrous K₂ CO₃ (0.48 g, 3.7 mmole), 18-crown-6 (0.098 g, 0.37 mmole)and acetonitrile (10 mL) is stirred under nitrogen for 15 minutes.2-Bromomethylnaphthalene (0.496 g, 4.07 mmole) is added and the mixtureis placed in an oil bath heated at 65°-70° C. for 10 hours (TLC,dichloromethane-ethyl acetate 8:2). A 10% excess of K₂ CO₃, crown etherand bromomethylnaphthalene is added and the heating is continued foranother 4 hours. The acetonitrile is evaporated and the residuedissolved in water and extracted with ethyl acetate (3×). The extractsare washed with 1N-NaOH and brine, dried (MgSO₄) and evaporated todryness. The crude product (1.49 g, waxy solid) is used as such in thenext step.

NMR (CDCl₃, 400 MHz): δ3.7 (s, 5H, OCH₃ +CH₂ COO), 5.32 (s, 2H, ArCH₂O), 7.08 (d, J 8.7 Hz, 2H, ArH), 7.4-7.56 (m, 5H, ArH), 7.63-7.68 (m,2H, ArH), 7.82-7.92 (m, 6H, ArH).

MS (m/z): 410 (M)⁺, 141 (b.p.).

B. 3-[4-(2-Naphthalenylmethoxy)benzoyl]benzene acetic acid

A solution of the ester (1.29 g, 3.15 mmole) of Step A, is treateddropwise with 1N-LiOH and the mixture is stirred under nitrogenovernight. The solvent is evaporated and the residue is dissolved inwater, acidified in the cold with 10% acetic acid (to pH 3) andextracted with ethyl acetate (3×). The extracts are dried (MgSO₄) andevaporated to dryness. The residue (1.24 g, quantitative yield) isrecrystallized by dissolving it in a relatively large volume of warmethyl acetate-dichloromethane followed by concentrating to half volume.The precipitate is collected and dried at 45° C. in vacuo (0.610 g,48.8%), m.p. 150°-152° C.

NMR (DMSO-d₆, 400 MHz): δ3.70 (s, 2H, CH₂ COO), 5.40 (s, 2H, ArCH₂),7.20 (d, 2H, ArH), 7.45-7.60 (m, 7H, ArH), 7.75 (d, 2H, ArH), 7.95 (m,3H, ArH), 8.02 (s, 1H, ArH), 12.47 (broad s, 1H, COOH).

MS (+FAB, m/z): 397 (M+H)⁺, 217, 141.

Analysis for: C₂₆ H₂₀ O₄ Calculated: C, 78.78; H, 5.09. Found: C, 78.12;H, 5.13.

EXAMPLE 5 5-Phenyl-4-[4-(2-Quinolinylmethoxy)phenyl]-2-oxazole propanoicacid

A. 4-Methoxybenzoin

To a solution of KCN (5 g) in water (35 mL) is added4-methoxybenzaldehyde (27.2 g, 0.2 mole), benzaldehyde (21.2 g, 0.2mole) and 95% ethanol (70 mL). The mixture is refluxed under nitrogenfor 4.5 hours and the ethanol removed in vacuo. Water (200 mL) is addedto the residue and then distilled off at reduced pressure (to removeremaining unreacted bezaldehyde). The procedure is repeated twice andthe residual water azeotroped with ethanol. The crude product (56.3 g,orange semi-solid) is purified by flashchromatography (on silicaMerck-60, preabsorbed in dichloromethane-ethyl acetate and eluted withhexane-ethyl acetate 8:2) to yield a light yellow solid (20.1 g, 41.5%),m.p. 99°-101° C.

NMR (CDCl₃, 400 MHz): δ3.82 (s, 3H, OCH₃), 4.62 (broad s, 1H, OH), 5.88(s, 1H, CHOH), 6.86 (d, 2H, J 8.94 Hz, ArH), 7.22-7.38 (m, 5H, ArH),7.91 (d, 2H, J 8.94 Hz, ArH).

MS (CI, m/z): 243 (b.p., M+H)⁺, 225, 197, 137 (M-PhCO)⁺.

B. 4-Methoxybenzoin hemisuccinate

A mixture of 4-methoxybenzoin (20 g, 0.083 mole) and succinic anhydride(9.1 g, 0.091 mole) in toluene (6 mL) is heated for 7 hours undernitrogen at 135° C. (internal temp.). The solution is poured into 0.5N-NaHCO₃, the organic layer was separated and reextracted with 0.5N-NaHCO₃. The combined extracts are washed with ether and then acidifiedin the cold with concentrated HCl. The liberated oil is extracted withethyl acetate (3×), the extracts washed with water and dried (MgSO₄).Removal of the solvent yields a yellow solid (20.89 g, 73.8%), m.p.104°-108° C. It is used in the next step without further purification.

NMR (CDCl₃, 400 MHz): δ2.72-2.82 (mm, 4H, CH₂ CH₂ COO), 3.82 (s, 3H,OCH₃), 6.86 (d, 2H, J 9.1 Hz, ArH), 7.34-7.46 (m, 5H, ArH), 7.92 (d, 2H,J 9.1 Hz, ArH).

MS (EI. m/z): 342 (M)⁺, 135 (b.p.).

C. 4-(4-Methoxyphenyl)-5-phenyl-2-oxazole-propanoic acid

A mixture of the crude 4-methoxybenzoin hemisuccinate (20.8 g, 0.061mole) of Step B, urea (8.7 g, 0.146 mole) and acetic acid (60 mL) isheated at reflux under nitrogen for 5.5 hours. The mixture is cooled andpoured into ice water. The liberated oil is extracted with ethyl acetate(3×). The extracts are washed with water until neutral and thenextracted with saturated sodium carbonate. The combined aqueous extractsare carefully acidified in the cold with concentrated HCl and extractedwith ethyl acetate. The organic extract is dried (MgSO₄) and evaporatedto dryness to provide a waxy yellow oil (19.6 g). Purification of theresidue by flash chromatography (on silica Merck-60, eluant:dichloromethane-ethyl acetate 8:2) yields a pale yellow solid (14.3 g,72.7%), m.p. 100°-101° C.

NMR (CDCl₃, 400 MHz): δ2.96 (t, 2H, CH₂ C), 3.20 (t, 2H, CH₂ COO), 3.83(s, 3H, OCH₃), 6.90 (d, 2H, ArH), 7.28-7.38 (m, 3H, ArH), 7.54-7.62 (m,4H, ArH).

MS (EI, m/z): 323 (M)⁺, 278 (b.p., M-COOH)⁺, 152, 77.

D. 4-(4-Hydroxyphenyl)-5-phenyl-2-oxazole-propanoic acid

To a solution of the methoxyacid (5.6 g, 17.3 mmole) of Step C, inacetic acid (55 mL) is added 48% HBr (84 mL) and the mixture is heatedat reflux under nitrogen for 8 hours (TLC, 1:1 hexane-ethyl acetate).After cooling, water is added and the solution extracted with ethylacetate (3×). The extract is dried (MgSO₄) and evaporated to dryness.The residue (brown waxy oil, 5.25 g, 99%) is used in the next stepwithout further purification. For analytical characterization a smallsample is flash-chromatographed (on silica Merck-60, eluant:dichloromethane-methanol 98:2 and 95:5).

NMR (DMSO-d₆, 400 MHz): δ2.75 (t, 2H, J 7.14 Hz, CH₂ C), 3.02 (t, 2H, J7.1 Hz, CH₂ COO), 6.77 (d, 2H, J 8.7 Hz, ArH), 7.35 (d, 2H, J 8.55 Hz,ArH), 7.41 (t, 3H, J 7.12 Hz, ArH), 7.50 (d, 2H, J 7 Hz, ArH), 9.64(broad s, exchangeable).

MS (EI, m/z): 309 (M)⁺, 264 (M-COOH)⁺, 121, 105, 77.

E. 5-Phenyl-4-(4-hydroxyphenyl)-2-oxazole propanoic acid methylester

A solution of the crude acid (5 g, 16.18 mmole) of Step D, in methanol(40 mL), containing a small amount of p-toluenesulfonic acid ·H₂ O (0.58g) is refluxed for 2.5 hours. The methanol is evaporated and the residueis partitioned between ethyl acetate and 20% NaCl. The extracts arewashed, dried (MgSO₄) and evaporated to yield a thick oil (ca. 4.8 g).The residue is flash-chromatographed (on silica Merck-60, preabsorbed indichloromethane, eluted with a dichloromethane-ethyl acetate gradientfrom 90:10 to 75:25) to yield a white solid (3.56 g, 68%), m.p.115°-116° C.

NMR (CDCl₃, 400 MHz): δ2.92 (t, 2H, J 7.4 Hz, CH₂ C), 3.20 (t, 2H, J 7.4Hz, CH₂ COO), 3.71 (s, 3H, OCH₃), 6.74 (d, 2H, J 8.59 Hz, ArH),7.26-7.36 (m, 3H, ArH), 7.40 (d, 2H, J 8.7 Hz, ArH), 7.54 (d, 2H, J 7.56Hz, ArH).

MS (EI, m/z): 323 (M)⁺, 264 (M-COOCH₃)⁺, 105, 77 (b.p.).

F. 5-Phenyl-4-[4-(2-quinolinylmethoxy)phenyl]-2-oxazole propanoic acidmethylester

A mixture of the ester (2.46 g, 7.61 mmole) of Step E, powderedanhydrous K₂ CO₃ (1.05 g, 7.60 mmole), 18-crown-6 (0.223 g, 0.843 mmole)and acetonitrile (33 mL, ex-sieves) is stirred at room temperature undernitrogen for 15 minutes. 2-Chloromethylquinoline (free base, freshlyprepared from the hydrochloride salt, 1.35 g, 7.60 mmole) is added andthe mixture is placed in an oil bath heated at 65° C. for 10 hours (N.B.A 10% excess of the chloromethylquinoline, 18-crown-6 and K₂ CO₃ isadded after 6 hours). The solvent is removed and the residue ispartitioned between ethyl acetate and water. The extracts are washed(brine), dried (MgSO₄) and evaporated to yield a yellow solid. The crudeproduct is flash chromatographed (on silica Merck-60, eluant: tolueneand then toluene-methanol 97.5:2.5) to provide the title compound (3.5g, quantitative yield).

NMR (CDCl₃, 400 MHz): δ2.90 (t, 2H, J ca. 7.2 Hz, CH₂ C), 3.16 (t, 2H,J7.2 Hz, CH₂ COO), 3.72 (s, 3H, OCH₃), 5.41 (s, 2H, ArCH₂ O), 7.02 (d,2H, J 8.8 Hz, ArH), 7.29-7.36 (m, ca. 4H, ArH), 7.54-7.84 (m, ca. 6H,ArH), 7.83 (d, 1H, J 8.1 Hz, ArH), 8.08 (t, 1H, J 8.5 Hz, ArH), 8.19 (d,1H, J 8.5 Hz, ArH).

MS (+FAB, m/z): 487 (M+Na)⁺, 465 (M+H)⁺.

G. 5-Phenyl-4-[4-(2-quinolinylmethoxy)phenyl]-2-oxazole propanoic acid

A solution of the ester (3.4 g, 7.32 mmole) of Step F, in drytetrahydrofuran (37 mL) is treated dropwise under nitrogen with 1N-LiOH(21.98 mL, 3 equiv.) and stirred at room temperature for 3 hours (TLC,dichloromethane-methanol 97:3 or toluene-methanol 95:5). The solvent isevaporated, the residue is dissolved in water, neutralized in the coldwith 10% acetic acid (to pH 5.5-6) and extracted with ethyl acetate. Theextracts are washed with brine, dried (MgSO₄) and evaporated to yield apale yellow solid (3.18 g, quantitative yield). The crude product isrecrystallized from warm ethyl acetate (containing enoughdichloromethane to obtain a clear solution) to yield a first crop ofcrystals (2.63 g, m.p. dec. 192°-194° C.). A second crop is obtained byconcentrating the mother liquors (0.327 g, m.p. dec. 192°-193° C.). Thecombined yield is 85.8%.

IR (KBr, cm⁻¹): 1720 (CO).

NMR (DMSO-d₆, 400 MHz): δ2.76 (t, 2H, J 7 Hz, CH₂ C), 3.03 (t, 2H, J 7Hz, CH₂ COO), 5.38 (s, 2H, ArCH₂ O), 7.11 (d, 2H, J 8.8 Hz, ArH),7.36-7.56 (m, 7H, ArH), 7.61 (t, 1H, ArH), 7.69 (d, 1H, J 8.5 Hz, ArH),7.78 (t, 1H, ArH), 8.00 (t, J 7.9 Hz, 2H, ArH), 8.42 (d, 1H, J 8.5 Hz,ArH).

MS (EI or CI, m/z): 451 (M+H)⁺, 310 (b.p.).

Analysis for: C₂₈ H₂₂ N₂ O₄ Calculated: C, 74.65; H, 4.92; N, 6.22.Found: C, 74.20; H, 4.86; N, 6.00.

EXAMPLE 6 4-[4-[2-Naphthalenylmethoxy]phenyl]5-phenyl-2-oxazolepropanoic acid

A. 4-[4-[2-Naphthalenylmethoxy]phenyl]-5-phenyl-2-oxazole propanoic acidmethylester

A mixture of the hydroxyester (1.5 g, 4.6 mmole) of Example 5E, powderedanhydrous K₂ CO₃ (0.636 g, 4.6 mmole), 18-crown-6 (0.123 g, 0.46 mmole)and acetonitrile (18 mL) is stirred at room temperature under nitrogenfor 15 minutes. 2-Bromomethylnaphthalene (1.13 g, 5.1 mmole) is addedand the mixture is placed in an oil bath heated at 70° C. for 8-9 hours(TLC, hexane-ethyl acetate 9:1 or dichloromethane-methanol 9:1). Thesolvent is evaporated and the residue dissolved in water and extractedwith ethyl acetate. The extracts are washed and dried (MgSO₄). Removalof the solvent yields a tan solid (2.17 g, quantitative yield). A sampleis recrystallized from methanol (containing enough dichloromethane toobtain a clear solution) by concentrating to small volume and cooling inan ice bath. The white solid is collected and dried overnight in vacuo,m.p. 134°-135° C.

IR (KBr, cm⁻¹): 1740 (CO).

NMR (CDCl₃ -400 MHz): δ2.89 (t, 2H, J 7.5 Hz, CH₂ C), 3.16 (t, 2H, J 7.5Hz, CH₂ COO), 3.71 (s, 3H, OCH₃), 5.2 (s, 2H, ArCH₂ O), 7.00 (d, 2H, J8.6 Hz, ArH), 7.25-7.35 (m, 3H, ArH), 7.46-7.58 (m, 7H, ArH), 7.8-7.9(m, 4H, ArH).

MS (CI, m/z): 464 (M+H)⁺, 324.

Analysis for: C₃₀ H₂₅ NO₄ : Calculated: C, 77.73; H, 5.44; N, 3.02.Found: C, 77.44; H, 5.36; N, 3.03.

B. 4-[4-(2-Naphthalenylmethoxy)phenyl]-5-phenyl-2-oxazole propanoic acid

A solution of the ester (1.49 g, 3.21 mmole) of Step A, in drytetrahydrofuran (18 mL) containing 1N-LiOH (9.6 mL) is stirred undernitrogen overnight at room temperature (TLC, 75:25 hexane-ethylacetate). The solvent is evaporated, the residue dissolved in water andacidified (to pH 5) with dilute HCl. The mixture is extracted with ethylacetate, the extracts are dried (MgSO₄) and evaporated to yield thecrude product (1.39 g, m.p. 145°-150° C.). For purification, it isdissolved in hot ethyl acetate (containing enough dichloromethane toobtain a clear solution), concentrated to half volume and precipitatedwith ether. The white solid melts at 151°-152° C. (1.07 g, 58%).

IR (KBr, cm⁻¹): 1720 (CO).

NMR (DMSO-d₆, 400 MHz): δ2.78 (t, 2H, CH₂ C), 3.03 (t, 2H, J 7 Hz, CH₂COO), 5.29 (s, 2H, ArCH₂ O), 7.10 (d, 2H, J 8.9 Hz, ArH), 7.34-7.60 (m,10H, ArH), 7.90-8.00 (m, 4H, ArH), 12.28 (s, 1H, COOH).

MS (EI, m/z): 450 (M+H)⁺, 310.

Analysis for: C₂₉ H₂₃ NO₄ : Calculated: C, 77.48; H, 5.15; N, 3.11.Found: C, 76.40; H, 5.16; N, 3.04.

EXAMPLE 7 4-[4-[(1-Methyl-1H-benzimidazol-2-yl)methoxy]phenyl]-5-phenyl-2-oxazole propanoic acid

A. 4-[4-[(1-Methyl-1H-benzimidazol-2-yl)methoxy]phenyl]-5-phenyl-2-oxazole propanoic acidmethylester

A mixture of the ester (0.5 g, 1.55 mmole) of Example 5E, powderedanhydrous K₂ CO₃ (0.214 g, 1.55 mmole), 18-crown-6 (0.0416 g, 0.155mmole) and acetonitrile (6 mL) is stirred under nitrogen at roomtemperature for 15 minutes. 2-Chloromethyl-1-methylbenzimidazole (0.307g, 1.7 mmole) is added and the mixture is placed in an oil bath heatedat 65°-70° C. for 4 hours (TLC, dichloromethane-ethyl acetate 9:1,iodine visualization). A 10% excess of K₂ CO₃,2-chloromethyl-1-methyl-benzimidazole and 18-crown-6 is added at thispoint and the heating continued for another 10 hours. The solvent isevaporated, the residue dissolved in water and extracted with ethylacetate. The extracts are washed, dried (MgSO₄) and evaporated todryness. The residue (1.64 g) is purified by flash-chromatography (onsilica Merck-60, preabsorbed in dichloromethane containing a smallamount of methanol, eluted with dichloromethane-ethyl acetate 8:2) toyield 1.03 g (71.2%) of a light yellow solid, m.p. 142°-144° C. (dec).

NMR (CDCl₃, 400 MHz): δ2.87 (t, 2H, J 7.1 Hz, CH₂ C), 3.16 (t, 2H, J 7.8Hz, CH₂ COO), 3.72 (s, 3H, COOCH₃), 3.90 (s, 3H, NCH₃), 5.41 (s, 2H,ArCH₂ O), 7.07 (d, 2H, J 8.8 Hz, ArH), 7.25-7.40 (m, 7H, ArH), 7.5-7.6(m, 3H, ArH), 7.78 (d, 1H, ArH).

MS (+C I, m/z): 468 (M+H)⁺, 324, 293, 147.

4-[4-[(1-Methyl-1H-benzimidazol-2-yl)methoxy]-5-phenyl-2-oxazolepropanoic acid

A solution of the ester (1 g, 2.14 mmole) of Step A, in tetrahydrofuran(13 mL) containing 1N-LiOH (6.42 mL) is stirred under nitrogen at roomtemperature for 1 hour (TLC, dichloromethane-ethanol 9:1). The solventis evaporated, water added and the pH adjusted to 6.5 with 10% aceticacid. The light yellow precipitate is collected, washed with water anddried in vacuo. It is redissolved in hot ethyl acetate (containingenough methanol to obtain a clear solution), concentrated to a smallervolume and cooled in an ice bath. The crystals are collected and dried(0.642 g, 66.2%, m.p. 222°-224° C.).

NMR (DMSO-d₆, 400 MHz): δ2.76 (t, 2H, J 7 Hz, CH₂ C), 3.03 (t, 2H, J 7Hz, CH₂ COO), 3.86 (s, 3H, NCH₃), 5.43 (s, 2H, ArCH₂ O), 7.14-7.66 (m,13H, ArH).

MS (CI, m/z): 454 (M+H)⁺, 147 (b.p.).

Analysis for: C₂₇ H₂₃ N₃ O₄ : Calculated: C, 71.51; H, 5.11; N, 9.27.Found: C, 71.62; H, 5.17; N, 9.40.

EXAMPLE 8N-Hydroxy-N-methyl-2-fluoro-4'-(2-quinolinylmethoxy)-[1,1'-biphenyl]-4-acetamide

To a solution of the acid of Example 2 (1.0 g, 2.58 mmol) in methylenechloride (20 ml) containing dimethylformamide (0.2 ml), 2.58 mmol) at 0°C. is added oxalyl chloride (0.506 ml, 5.80 mmol), dropwise. After thereaction mixture is stirred for 1 hour, it is added dropwise to asolution of N-methylhydroxylamine hydrochloride (0.861 g, 10.32 mmol) intriethylamine (1.87 ml, 13.41 mmol), tetrahydrofuran (10 ml) and water(2.0 ml) at 0° C. After overnight stirring, the reaction mixture ispoured into 2N HCl, the ensuing solid is collected and recrystallizedfrom ethanol. The crystals are then flash chromatographed eluting withethyl acetate-hexane (3:2) followed by ethyl acetate-ethanol (99:1). Thematerial at this point is still contaminated with a minor impurity whichis removed by conversion of the material to the hydrochloride salt,followed by washing with ethyl acetate, basification and finalextraction with ethyl acetate to afford white crystals, m.p. 153°-155°C.

Analysis for: C₂₅ H₂₁ N₂ O₃ F: Calculated: C, 72.10; H, 5.08; N, 6.73.Found: C, 71.95; H, 5.07; N, 6.39.

EXAMPLE 9 2-Fluoro-4'-(2-quinolinylmethoxy)[1,1'-biphenyl]-4-aceticacid, 2-amino-2-hydroxymethyl-1,3-propane diol

A solution of the compound of Example 2 (3.17 g, 8.2 mmole) and2-amino-2-hydroxymethyl-1,3-propane diol [TRIS, 0.99 g, 8.2 mmole] in 60mL of methanol is concentrated to a syrup. Following dilution withethylacetate (250 mL), the crystalline precipitate is collected anddried to give 3.18 g of the title salt. The product is micronized to afine white powder, m.p. 168°-169° C. (77.5% yield).

Analysis for: C₂₈ H₂₉ FN₂ O₆ : Calculated: C, 66.13; H, 5.75; N, 5.51.Found: C, 65.75; H, 5.79; N, 5.49.

EXAMPLE 10 5-Phenyl-4-[4-quinolinylmethoxy)-phenyl]-2-oxazole propionicacid, 2-amino-2-hydroxymethyl-1,3-propane diol

To a solution of the compound of Example 5 (0.359 g, 0.796 mmole) inboiling ethanol (35 mL) is added 2-amino-2-hydroxymethyl-1,3-propanediol [TRIS, 0.0965 g, 0.796 mmole] in 0.5 mL of water. After two hours,the mixture is refrigerated. The crystalline precipitate is collectedand dried to give 0.396 g of the title salt, m.p. 170°-171° C.

Analysis for: C₃₂ H₃₃ N₃ O₇ : Calculated: C, 67.00; H, 5.75; N, 7.32.Found: C, 66.68; H, 5.77; N, 7.31.

EXAMPLE 11 4'-(2-Benzothiazolylmethoxy)-4-diphenylacetic acid, ethylester

A. 4'-Hydroxy-4-diphenylacetic acid, ethyl ester

A solution containing 4'-hydroxy-4-diphenylacetic acid (6.7 g, 28.0mmol), absolute ethanol (300 ml) and concentrated sulfuric acid (5 ml)is refluxed for 2 hours. The reaction mixture is cooled to roomtemperature, concentrated under reduced pressure, diluted with water(200 ml) and extracted with ethyl acetate (200 ml; 3 times). Thecombined ethyl acetate extract is washed with 1N sodium hydroxide (200ml), water (200 ml) and brine (200 ml), is dried over anhydrousmagnesium sulfate and is concentrated under reduced pressure to afford6.9 g of crude solids. The solids are purified by chromatography (silicagel; 30% ethyl acetate in hexane) to give 6.7 g (95.0%) of whitecrystalline product, m.p. 125°-127° C.

Analysis for: C₁₆ H₁₆ O₃ : Calculated: C, 74.98; H, 6.29. Found: C,74.62; H, 6.22.

B. 4'-(2-Benzothiazolylmethoxy)-4-diphenylacetic acid, ethyl ester

A slurry of 4'-hydroxy-4-diphenylacetic acid, ethyl ester (6.7 g, 26.0mmol, Part A.) and cesium carbonate (9.0 g, 28.0 mmol) indimethylsulfoxide (150 ml) is stirred at room temperature. After 30minutes, 2-(chloromethyl)-benzothiazole (4.2 g, 27.0 mmol) is added andthe mixture is stirred for 18 hours. The reaction mixture is poured intoice-water (200 ml) and is extracted with ethyl acetate (300 ml, 3times). The combined ethyl acetate extract is washed sequentially with0.1N sodium hydroxide (200 ml), water (200 ml) and brine (200 ml), isdried over anhydrous magnesium sulfate, and concentrated under reducedpressure to give 8.0 g of crude solids. The solids are purified bychromatography (silica gel, 30% ethyl acetate in hexane) to afford 4.0 g(39.2%) of white crystalline produce, m.p. 133°-134° C.

Analysis for: C₂₄ H₂₁ NO₃ S: Calculated: C, 71.44; H, 5.25; N, 3.47.Found: C, 71.36; H, 5.25; N, 3.35.

EXAMPLE 12 4'-(Benzothiazolylmethoxyl)-4-diphenylacetic acid

A mixture of 4'-(benzothiazolylmethoxy)-diphenylacetic acid, ethyl ester(4.0 g, 10.0 mmol), 1N sodium hydroxide (15 ml, 15.0 mmol), methanol(200 ml) and tetrahydrofuran (200 ml) is refluxed for 18 hours. Thereaction mixture is cooled, concentrated under reduced pressure, isdiluted with water (500 ml) and with stirring, is acidified with 2Nhydrochloric acid. After stirring for two hours, the product iscollected by filtration and after vacuum drying, 3.8 g (99%) of solidsis obtained. A portion of this material (0.5 g) is recrystallized fromacetic acid, m.p. 208°-209° C.

Analysis for: C₂₂ H₁₇ NO₃ S: Calculated: C, 70.38; H, 4.56; N, 3.73.Found: C, 70.04; H, 4.56; N, 3.72.

EXAMPLE 134'-(Benzothiazolylmethoxy)-4-diphenyl-N-hydroxy-N-methyl-acetamide

A mixture of 4'-(benzothiazolylmethoxy)-4-diphenylacetic acid (1.0 g,3.0 mmol), methylene chloride (50 ml) and dimethylacetamide (0.21 ml) iscooled to 5° C. and with stirring, a solution of oxalyl chloride (0.6ml) in methylene chloride (10 ml) is added slowly. After stirring atroom temperature for 30 minutes, the reaction mixture is poured into asolution containing tetrahydrofuran (13 ml), water (1.2 ml),triethylamine (2.0 ml) and N-methylhydroxylamine hydrochloride (1.0 g,12.0 mmol). After stirring for 1 hour the reaction mixture is dilutedwith methylene chloride (100 ml), is poured into 2N hydrochloric acid(100 ml) and is extracted. The aqueous layer is washed again withmethylene chloride (100 ml). The combined methylene chloride extract iswashed with water (100 ml) and brine (100 ml), is dried over anhydrousmagnesium sulfate and is concentrated under reduced pressure to afford1.0 g of crude solid product. The solids are recrystallized fromacetonitrile to give 0.6 g (60%) of a yellowish-colored crystallinesolid, m.p. 176°-179° C.

Analysis for: C₂₃ H₂₀ N₂ O₃ S: Calculated: C, 68.30; H, 4.98; N, 6.93.Found: C, 68.70; H, 4.89; N, 6.62.

EXAMPLE 14N-Hydroxy-4'-(2-benzothiazolylmethoxy)[1,1'-biphenyl]-4-acetamide

The title compound is prepared using the procedure of Example 13employing the carboxylic acid from Example 12 and substitutinghydroxylamine for N-methylhydroxylamine. Normal workup gives 1.0 g ofcrude solid. The solid is recrystallized from acetonitrile to give 0.60g (60.0%) of crystalline product, m.p. 176°-179° C.

Analysis for: C₂₂ H₁₈ N₂ O₃ S.0.5 H₂ O: Calculated: C, 66.90; H, 4.72;N, 7.09. Found: C, 67.12; H, 4.68; N, 7.36.

EXAMPLE 15N-Hydroxy-N-isopropyl-4'-(2-benzothiazolylmethoxy)[1,1'-biphenyl]-4-acetamide

The title compound is prepared using the procedure of Example 13employing the carboxylic acid from Example 12 substitutingN-isopropylhydroxylamine for N-methylhydroxylamine. Normal workup gives0.6 g of crude solid. The solid is recrystallized from acetonitrile togive 0.20 g (14.2%) of beige crystalline product, m.p. 203°-204° C.

Analysis for: C₂₅ H₂₄ N₂ O₃ S: Calculated: C, 69.42; H, 5.59; N, 6.48.Found: C, 69.44; H, 5.52; N, 6.09.

EXAMPLE 16N-Hydroxy-N,α-dimethyl-4'-(2-benzothiazolylmethoxy)[1,1'-biphenyl]-4-acetamide

A. α-Methyl-4'-(methoxy)[1,1'-biphenyl]-4-acetic acid, ethyl ester

The known starting material, 4'-methoxy-4-biphenylacetic acid (J. Chem.Soc. 1959, 557) is first converted to its ethyl ester by Fisheresterification with ethanol and concentrated sulfuric acid. To asolution of 4'-methoxy-4-biphenylacetic acid, ethyl ester (30.0 g, 0.110mol) in tetrahydrofuran (400 mL) at -78° C. is added slowly, 2.01Mlithium diisopropylamide (63 mL). The mixture is stirred for 30 minutesand then methyl iodide (30 mL) is added rapidly. The reaction mixture iswarmed to 0° C. for 30 minutes, then at room temperature for 3 hours.The mixture is poured into water (2 L) and is extracted with ethylacetate (3×1 L). The combined ethyl acetate extract is washed with 1NHCl (1 L), water (1 L) and brine (1 L), dried over MgSO4 and isconcentrated under reduced pressure to give 48 g of crude yellow oil.Purification of the product by column chromatography (12% ethyl acetatein hexane) gives 22.0 g (69.6%) of crystalline material, m.p. 52°-54° C.

Analysis for: C₁₈ H₂₀ O₃ : Calculated: C, 76.03; H, 7.09. Found: C,76.33; H, 7.08.

B. α-Methyl-4'-(hydroxy)[1,1'-biphenyl]-4-acetic acid

A mixture containing α-methyl-4'-(methoxy)[1,1'-biphenyl]-4-acetic acid,ethyl ester (22.0 g, 77.4 mmol), acetic acid (400 mL) and 48%hydrobromic acid (80 mL) is refluxed for 18 hours. The solution isconcentrated under reduced pressure to one-third the volume and theproduct crystallizes from the solution. The solid is filtered and driedto give a quantitative yield. A portion of this material isrecrystallized from acetonitrile and a white solid is obtained, m.p.205°-206° C. MS (EI m/z): 242 (M)+, (b.p., M-CO2H)+.

C. α-Methyl-4'-(hydroxy)[1,1'-biphenyl]-4-acetic acid, ethyl ester

A mixture of α-methyl-4'-(hydroxy)[1,1'-biphenyl]-4-acetic acid (22.0 g,90.8 mmol) in ethanol (500 mL) and concentrated sulfuric acid (5.0 mL)is refluxed for 30 hours. The solution is concentrated under reducedpressure, is diluted with water (300 mL) and is extracted with ethylacetate (3×300 mL). The combined ethyl acetate extract is washed withwater (400 mL) and brine (400 mL), dried over MgSO4 and is concentratedunder reduced pressure to give 20 g of crude product. Purification ofthis material by column chromatography (25% ethyl acetate in hexane)followed by crystallization from ethyl acetate and hexane gives 18.0 g(73.5%) of crystalline product, m.p. 124°-125° C., MS(CI⁺ m/z):271[M+H]⁺.

Analysis for: C₁₇ H₁₈ O₃ : Calculated: C, 75.53; H, 6.71. Found: C,75.07; H, 6.66.

D. α-Methyl-4'-(2-benzothiazolylmethoxy)[1,1'-biphenyl]-4-acetic acid,ethyl ester

The title compound is prepared using the procedure of Example 11Bemploying the above hydroxy-ester (5.0 g, 18.5 mmol). Normal workupgives a crude solid which is purified by column chromatography (30%ethyl acetate in hexane) to afford the desired product, 6.5 g (84.4%). Aportion of the solid is recrystallized from ethyl acetate and hexane,m.p. 114°-115° C.

Analysis for: C₂₅ H₂₃ NO₃ S: Calculated: C, 71.91; H, 5.55; N, 3.35.Found: C, 72.28; H, 5.54; N, 3.29.

E. α-Methyl-4'-(2-benzothiazolylmethoxy)[1,1'-biphenyl]-4-acetic acid

A solution of α-methyl-4'-(benzothiazolylmethoxy)-[1,1'-biphenyl]aceticacid, ethyl ester (6.0 g, 14.4 mmol), methanol (200 mL), tetrahydrofuran(200 mL) and 1N NaOH (25 mL) is refluxed for 18 hours. The reactionmixture is cooled to 0° C. and the product crystallizes from thesolution. Filtration of the solid gives 4.0 g (67.8%) of product (m.p.greater than 250° C.). Theα-methyl-4'-(benzothiazolylmethoxy)[1,1'-biphenyl]-4-acetic acid, sodiumsalt (3.8 g, 9.2 mmol) is dissolved in a mixture of tetrahydrofuran (250mL) and methanol (250 mL) and 1N HCl (5.0 mL) is added. The solution isdiluted with water (350 mL) and the product crystallizes from thereaction mixture. The solid is collected by filtration to afford thecrude product. Recrystallization of the solid from acetonitrile gives3.6 g (94.4%) of white crystalline product, m.p. 199°-200° C.

Analysis for: C₂₃ H₁₉ NO₃ S: Calculated: C, 70.93; H, 4.92; N, 3.60.Found: C, 70.80; H, 4.81; N, 3.77.

F.N-Hydroxy-N,α-dimethyl-4'-(2-benzothiazolylmethoxy)[1,1'-biphenyl]-4-acetamide

The title compound is prepared using the procedure of Example 13employing the carboxylic acid from the previous step. Normal workupgives 2.0 g of crude solid. The solid is recrystallized fromacetonitrile to give 1.6 g (76.2%) of crystalline product, m.p.160°-161° C.

Analysis for: C₂₄ H₂₂ N₂ O₃ S: Calculated: C, 68.55; H, 5.75; N, 6.66.Found: C, 68.38; H, 5.41; N, 6.57.

EXAMPLE 17N-Hydroxy-N,,a,-dimethyl-4'-(2-benzothiazolylmethoxy)[1,1'-biphenyl]-4-acetamide,sodium salt, methanol solvate

A solution containingN-hydroxy-N,α,-dimethyl-4'-(2-benzothiazolylmethoxy)[1,1'-biphenyl]-4-acetamide(0.60 g, 1.43 mmol), in hot acetonitrile (150 mL) is treated with sodiummethoxide (0.079 g, 1.43 mmol) in methanol (5 mL) and the productcrystallizes from the solution. After storing the mixture overnight at0° C., filtration of the white solid gives 0.59 g (93.7%) of product,(m.p. greater than 250° C.).

Analysis for: C₂₄ H₂₁ N₂ O₃ SNa. CH₃ OH: Calculated: C, 63.54; H, 5.33;N, 5.93. Found: C, 63.19; H, 5.24; N, 6.31.

EXAMPLE 18N-Hydroxy-N-methyl-4'-[(2-phenylthiazol-4-yl)methoxy][1,1'-biphenyl]-4-acetamide

A. 4'-[(2-Phenylthiazol-4-yl)methoxy][1,1'-biphenyl]-4-acetic acid,ethyl ester

The title compound is prepared using the procedure of Example 11Bemploying the hydroxy-ester from Example 11A (6.0 g, 26.3 mmol) andsubstituting 4-(chloromethyl)-2-phenylthiazole for2-(chloromethyl)benzothiazole. Normal workup gives a crude solid whichis purified by crystallization from hexane to afford 7.3 g (61.3%) ofyellow colored product, m.p. 115°-117° C.

Analysis for: C₂₆ H₂₃ NO₃ S: Calculated: C, 72.70; H, 5.40; N, 3.26.Found: C, 72.36; H, 5.39; N, 3.42.

B. 4'-[(2-Phenylthiazol-4-yl)methoxy][1,1'-biphenyl]-4-acetic acid

The title compound is prepared using the procedure of Example 16, part Eemploying the previous ester. The product crystallizes from thesolution. The solid is collected by filtration to afford 4.2 g (88.6%)of product, m.p. 185°-189° C.

Analysis for: C₂₄ H₁₉ NO₃ S: Calculated: C, 71.80; H, 4.77; N, 3.49.Found: C, 71.71; H, 4.80; N, 3.76.

C.N-Hydroxy-N-methyl-4'-[(2-phenylthiazol-4-yl)methoxy][1,1'-biphenyl]-4-acetamide

The title compound is prepared using the procedure of Example 13employing the previous acid. Normal workup affords 0.8 g of crude solid.The solid is recrystallized from acetonitrile to give 0.5 g (62.0%) ofcrystalline product, m.p. 159°-161° C.

Analysis for: C₂₅ H₂₂ N₂ O₃ S: Calculated: C, 69.75; H, 5.15; N, 6.51.Found: C, 69.49; H, 5.15; N, 6.29.

EXAMPLE 19N-Hydroxy-N-methyl-4'-[(2-phenylthiazol-4-yl)methoxy][1,1'-biphenyl]-4-acetamide,sodium salt, sesquihydrate

The title compound is prepared using the procedure of Example 17employing the previous hydroxamic acid. The product crystallizes fromthe solution. After storing the mixture overnight at 0° C., filtrationof the white solid gives 0.18 g (90.4%) of product, m.p. 230° C. (dec.).

Analysis for: C₂₄ H₂₁ N₂ O₃ SNa.1.5 H₂ O: Calculated: C, 62.60; H, 5.04;N, 5.83. Found: C, 62.54; H, 4.77; N, 5.50.

EXAMPLE 20N-Hydroxy-N-isopropyl-4'-[(2-phenylthiazol-4-yl)methoxy][1,1'-biphenyl]-4-acetamide

The title compound is prepared using the procedure of Example 13employing the acid from Example 18 and substitutingN-isopropylhydroxylamine for N-methylhydroxylamine. Normal workup gives0.8 g of crude solid. The solid is recrystallized from acetonitrile togive 0.5 g (56.0%) of crystalline product, m.p. 174°-175° C.

Analysis for: C₂₅ H₂₂ N₂ O₃ S: Calculated: C, 70.72; H, 5.72; N, 6.11.Found: C, 70.90; H, 5.80; N, 6.03.

EXAMPLE 21N-Hydroxy-N,α-dimethyl-4'-[(2-phenylthiazol-4-yl)methoxy][1,1'-biphenyl]-4-acetamide

A.α-Methyl-4'-[(2-phenylthiazol-4-yl)methoxy][1,1'-biphenyl]-4-aceticacid,ethyl ester

The title compound is prepared using the procedure of Example 11Bemploying the hydroxy-ester from part C of Example 16 and substituting4-(chloromethyl)-2-phenylthiazole for 2-(chloromethyl)benzothiazole.Normal workup gives 8.0 g of a crude solid which is purified by columnchromatography (30% ethyl acetate in hexane), affording 6.5 g (79.3%) ofwhite crystalline product, m.p. 85°-86° C.

Analysis for: C₂₇ H₂₅ NO₃ S: Calculated: C, 73.11; H, 5.68; N, 3.16.Found: C, 72.86; H, 5.67; N, 2.93.

B.α-Methyl-4'-[(2-phenylthiazol-4-yl)methoxy][1,1'-biphenyl]-4-aceticacid

The title compound is prepared using the procedure of part E of Example16 employing the above ester. The product crystallizes from thesolution. The solid is collected by filtration to afford 4.2 g (83.0%)of product, m.p. 203°-204° C.

Analysis for: C₂₅ H₂₁ NO₃ S: Calculated: C, 72.27; H, 5.09; N, 3.37.Found: C, 72.03; H, 4.95; N, 3.41.

C.N-Hydroxy-N,a-dimethyl-4'-[(2-phenylthiazol-4-yl)methoxy]-[1,1'-biphenyl]4-acetamide

The title compound is prepared using the procedure of Example 13employing the previously prepared acid. Normal workup gives 2.0 g ofcrude solid. The solid is recrystallized from acetonitrile to give 1.6 g(76.2%) of crystalline product, m.p. 180°-181° C.

Analysis for: C₂₆ H₂₄ N₂ O₃ S: Calculated: C, 70.25; H, 5.44; N, 6.30.Found: C, 69.91; H, 5.35; N, 6.19.

EXAMPLE 22N-Hydroxy-N,α-dimethyl-4'-[(2-phenylthiazol-4-yl)methoxy][1,1'-biphenyl]-4-acetamide,sodium salt, hydrate

The title compound is prepared using the procedure of Example 17employing the previously synthesized hydroxamic acid. After storing themixture overnight at 0° C., filtration of the white solid gives 0.61 g(82.8%) of product, m.p. 166° C. (dec.).

Analysis for: C₂₆ H₂₃ N₂ O₃ SNa.1 H₂ O: Calculated: C, 64.44; H, 5.20;N, 5.78. Found: C, 64.79; H, 5.10; N, 6.32.

EXAMPLE 23N-Hydroxy-N,α-dimethyl-4'-[(1-methyl-1H-benzimidazol-2-yl)methoxy]-[1,1'-biphenyl]-4-acetamide

A.α-Methyl-4'-[(1-methyl-1H-benzimidazol-2-yl)[methoxy][1,1'-biphenyl]-4-aceticacid, ethyl ester, quarter hydrate

The title compound is prepared using the procedure of Example 11Bemploying the hydroxy-ester from part C of Example 16 and substitutingN-methyl-2-(chloromethyl)benzimidazole for2-(chloromethyl)benzothiazole. Normal workup gives 8.0 g of crude solidwhich is purified by column chromatography (65% ethyl acetate in hexane)to afford 5.1 g (66.5%) of product. A portion of this material isrecrystallized from ethyl acetate to give white crystalline solid, m.p.136°-138° C., MS(EI⁺ m/z): 414 (m)⁺.

Analysis for: C₂₆ H₂₆ N₂ O₃.0.25 H₂ O: Calculated: C, 74.53; H, 6.37; N,6.68. Found: C, 74.53; H, 6.23; N, 6.64.

B.α-Methyl-4'-[(1-methyl-1H-benzimidazol-2-yl)-methoxy][1,1'-biphenyl]-4-aceticacid hydrate

The title compound is prepared using the procedure of part E of Example16 employing the above ester. The precipitated solid is collected byfiltration to afford 2.0 g (48%) of product. A portion of this materialis recrystallized from acetonitrile to give purified crystals, m.p.228°-230° C.

Analysis for: C₂₄ H₂₂ N₂ O₃.H₂ O: Calculated: C, 71.27; H, 5.98; N,6.92. Found: C, 71.59; H, 5.60; N, 7.17.

C.N-Hydroxy-N,α-dimethyl-4'-[(1-methyl-1H-benzimidazol-2-yl)methoxy][1,1'-biphenyl]-4-acetamide

The title compound is prepared using the procedure of Example 13employing the previously prepared acid. Normal workup affords 2.2 g ofcrude solid which is recrystallized from acetonitrile to give 1.3 g(59.0%) of crystalline product, m.p. 195°-197° C.

Analysis for: C₂₅ H₂₅ N₃ O₃ : Calculated: C, 72.27; H, 6.06; N, 10.11.Found: C, 72.15; H, 6.02; N, 10.60.

EXAMPLE 24N-Hydroxy-N,α-dimethyl-4'-[(1-methyl-1H-benzimidazol-2-yl)methoxy]-[1,1'-biphenyl]-4-acetamide,hydrochloride salt

A solution containingN-hydroxy-N,α-dimethyl-4'-[(1-methyl-1H-benzimidazol-2-yl)methoxy]-[1,1'-biphenyl]-4-acetamide(0.2 g, 0.48 mmol) in warm methanol (100 mL) is treated with 1M hydrogenchloride in diethyl ether (3 mL). The solution is concentrated underreduced pressure to a solid residue. This material is crystallized froma mixture of ethanol and diethyl ether to give 0.2 g (92.2%) of whitecrystalline product, m.p. 131° C. (dec.).

Analysis for: C₂₅ H₂₅ N₃ O₃.HCl: Calculated: C, 66.44; H, 5.80; N, 9.30.Found: C, 66.06; H, 6.14; N, 8.95.

EXAMPLE 25N-Hydroxy-N-methyl-2-phenyl-α-[4'-[(2-phenylthiazol-4-yl)methoxy]-[1,1'-biphenyl]-4-yl]-thiazolepropanamide

A.4'-[(2-Phenylthiazol-4-yl)methoxy]-α-[(2-phenylthiazol-4-yl)methyl][1,1'-biphenyl]-4-aceticacid, ethyl ester

A slurry of the hydroxy-ester (6.9 g, 30.2 mmol) from Example 11A andcesium carbonate (15.0 g, 46.0 mmol) in dimethylsulfoxide (150 mL) isstirred at room temperature. After 30 minutes,4-(chloromethyl)-2-phenylthiazole (12.6 g, 60.2 mmol) is added and themixture is stirred for 18 hours. The reaction mixture is poured intowater (800 mL) and extracted with ethyl acetate (3×500 mL). The combinedethyl acetate extract is washed with water (300 mL), brine (300 mL),dried over MgSO₄, and concentrated under reduced pressure to give 10.0 gof a crude solid. A 5 g portion of this material is purified by columnchromatography (0.1% methanol in methylene chloride) followed bycrystallization from ethyl acetate and hexane to afford 2.0 g of whitecrystalline product, m.p. 85°-87° C.

Analysis for: C₃₆ H₃₀ N₂ O₃ S₂ Calculated: C, 71.73; H, 5.02; N, 4.65.Found: C, 71.67; H, 5.13; N, 4.98.

B.4'-[(2-Phenylthiazol-4-yl)methoxy]-α-[(2-phenylthiazol-4-yl)methyl][1,1'-biphenyl]-4-aceticacid

The title compound is prepared using the procedure of part E of Example16 employing the above ester. Normal workup affords a crude solid whichis crystallized from acetic acid to afford 1.2 g (78.9%) of product,m.p. 195°-197° C.

Analysis for: C₃₄ H₂₆ N₂ O₃ S₂ : Calculated: C,71.06; H,4.56; N,4.87.Found: C,71.04; H,4.67; N,4.93.

C.N-Hydroxy-N-methyl-2-phenyl-α-[4'-[(2-phenylthiazol-4-yl)methoxy]-[1,1'-biphenyl]-4-yl]-thiazolepropanamide

The title compound is prepared using the procedure of Example 13employing the previously prepared acid. Normal workup affords 0.6 g(75.0%) of product, m. p. 60°-75° C.

Analysis for: C₃₅ H₂₉ N₃ O₃ S₂.H₂ O: Calculated: C,67.66; H,5.03;N,6.76. Found: C,67.69; H,4.96; N,6.64.

EXAMPLE 264'-(Benzothiazolylmethoxy)-2-fluoro-N-hydroxy-N-methyl-[1,1'-biphenyl]-4-acetamide

A. 4'-(Benzothiazolylmethoxy)-2-fluoro[1,1'-biphenyl]-4-acetic acidmethyl ester 0.1 hydrate

The title compound is prepared using the method of Example 2Fsubstituting 2-(chloromethyl)benzothiazole for2-(chloromethyl)quinoline. Normal workup followed by recrystallizationfrom methanol affords 1.2 g (67%) of white crystals, m.p. 116°-118° C.

Analysis for: C₂₃ H₁₈ NO₃ FS.0.1 H₂ O: Calculated: C, 67.50; H, 4.48; N,3.42. Found: C, 67.24; H, 4.70; N, 3.52.

B. 4'-(Benzothiazolylmethoxy)-2-fluoro[1,1'-biphenyl]-4-acetic acid

The title compound is prepared using the method of Example 2G employingthe above ester. Normal workup affords 0.87 g (70%) of white crystals,m.p. 171°-173° C.

Analysis for: C₂₂ H₁₆ NO₃ FS: Calculated: C, 67.16; H, 4.10; N, 3.56.Found: C, 67.23; H, 4.25; N, 3.55.

C.4'-(Benzothiazolylmethoxy)-2-fluoro-N-hydroxy-N-methyl-[1,1'-biphenyl]-4-acetamide

The title compound is prepared using the methods of Example 8 employingthe above carboxylic acid and omitting the dimethylformamide and aqueoustetrahydrofuran. Quenching the reaction by addition of water affords0.35 g (46%) of a white solid, m.p. 178°-180° C.

Analysis for: C₂₃ H₁₉ N₂ O₃ FS: Calculated: C, 65.39; H, 4.53; N, 6.63.Found: C, 65.58; H, 4.47; N, 6.57.

EXAMPLE 272-Fluoro-N-hydroxy-N-methyl-4'-[2-phenyl-4-thiazolyl)methoxy]-[1,1'-biphenyl]-4-acetamide

A. 2-Fluoro-4'-[2-phenyl-4-thiazolyl)methoxy]-[1,1'-biphenyl]-4-aceticacid methyl ester

The title compound is prepared using the method of Example 2Fsubstituting 4-(chloromethyl)-2-phenyl-thiazole for2-(chloromethyl)quinoline. Normal workup followed by flashchromatography, eluting with 7:3 ethyl acetate-hexane), affords 0.69 g(27%) of white crystals, m.p. 87°-88° C.

Analysis for: C₂₅ H₂₀ NO₃ FS: Calculated: C, 69.27; H, 4.65; N, 3.23.Found: C, 69.03; H, 4.73; N, 2.99.

B. 2-Fluoro-4'-[2-phenyl-4-thiazolyl)methoxy]-[1,1'-biphenyl]-4-aceticacid

The title compound is prepared using the method of Example 2G employingthe above ester. Normal workup affords 3.6 g (93%) of white crystals,m.p. 155°-158° C.

Analysis for: C₂₄ H₁₈ NO₃ FS: Calculated: C, 68.72; H, 4.33; N, 3.34.Found: C, 68.85; H, 4.29; N, 2.94.

C.2-Fluoro-N-hydroxy-N-methyl-4'-[2-phenyl-4-thiazolyl)methoxy]-[1,1'-biphenyl]-4-acetamide

The title compound is prepared using the method of Example 8 employingthe above carboxylic acid. Normal workup followed by trituration withethyl acetate-hexane affords 0.37 g (11%) of a white solid, m.p.116°-119° C.

Analysis for: C₂₅ H₂₁ N₂ O₃ FS: Calculated: C, 66.95; H, 4.72; N, 6.25.Found: C, 66.30; H, 4.85; N, 6.25.

EXAMPLE 282-Fluoro-N-hydroxy-N-methyl-4'-(2-pyridinylmethoxy)-[1,1'-biphenyl]-4-acetamide

A.2-Fluoro-N-hydroxy-N-methyl-4'-(2-pyridinylmethoxy)-[1,1'-biphenyl]-4-aceticacid

The title compound is prepared using the methods of Examples 2F and Gsubstituting 2-(chloromethyl)pyridine for 2-(chloromethyl)quinoline.Normal workup of the ester followed by flash chromatography, elutingwith 1:1 ethyl acetatehexane, affords 1.1 g (29%) of the ester which issubsequently hydrolyzed to afford 0.94 g (89%) of the title compound asa white solid, m.p. 166°-169° C.

Analysis for: C₂₀ H₁₆ NO₃ F: Calculated: C, 71.21; H, 4.78; N, 4.15.Found: C, 71.28; H, 4.74; N, 3.96.

B.2-Fluoro-N-hydroxy-N-methyl-4'-(2-pyridinylmethoxy)-[1,1'-biphenyl]-4-acetamide

The title compound is prepared using the method of Example 8 employingthe above carboxylic acid. Normal workup followed by flashchromatography, eluting with 6:4 ethyl acetate-hexane, andrecrystallization from ethyl acetate-hexane affords 0.07 g (10%) of awhite solid, m.p. 137°-139° C.

Analysis for: C₂₁ H₁₉ N₂ O₃ F: Calculated: C, 68.84; H, 5.23; N, 7.65.Found: C, 68.74; H, 5.60; N, 6.75.

EXAMPLE 292-[2-Fluoro-4'-(1-methyl-1H-benzimidazol-2-ylmethoxy)biphenyl-4-yl]-N-hydroxy-N-methyl-4-acetamide

A.2-[2-Fluoro-4'-(1-methyl-1H-benzimidazol-2-ylmethoxy)-biphenyl-4-yl]-4-aceticacid

The title compound is prepared using the methods of Example 2F and Gsubstituting 2-(chloromethyl)1-methyl-1H-benzoimidazole for2-(chloromethyl)quinoline. Normal workup followed by recrystallizationfrom ethyl acetate affords white crystals, m.p. 224°-226° C.

Analysis for: C₂₃ H₁₉ N₂ O₃ F: Calculated: C, 70.76; H, 4.91; N, 7.48.Found: C, 70.93; H, 4.89; N, 7.49.

B.2-[2-Fluoro-4'-(1-methyl-1H-benzimidazol-2-ylmethoxy)-biphenyl-4-yl]-N-hydroxy-N-methyl-4-acetamide

The title compound is prepared using the method of Example 8. Normalworkup followed by flash chromatography, eluting with 6:4 ethylacetate-hexane, affords 0.1 g (10%) of a white solid, m.p. 203°-205° C.

Analysis for: C₂₄ H₂₂ N₃ O₃ F: Calculated: C, 68.72; H, 5.29; N, 10.02.Found: C, 68.37; H, 5.35; N, 9.78.

EXAMPLE 302-{3-[4-(Benzothiazol-2-ylmethoxy)-benzoyl]-phenyl}-N-hydroxy-N-methyl-4-acetamide0.6 ethyl acetate solvate

A. 2-{3-[4-(Benzothiazol-2-ylmethoxy)-benzoyl]-phenyl}-4-acetic acidmethyl ester

The title compound is prepared using the method of Example 3Gsubstituting 2-(chloromethyl)benzothiazole for2-(chloromethyl)quinoline. Normal workup followed by recrystallizationfrom ethyl acetate-hexane affords 3.3 g (53%) of the title compound.

B. 2-{3-[4-(Benzothiazol-2-ylmethoxy)-benzoyl]-phenyl}-4-acetic acid

The title compound is prepared using the method of Example 3H employingthe above ester. Normal workup affords 2.5 g (79%) of the acid as awhite solid.

C.2-{3-[4-(Benzothiazol-2-ylmethoxy)-benzoyl]-phenyl}-N-hydroxy-N-methyl-4-acetamide0.6 ethyl acetate solvate

The title compound is prepared using the method of Example 8 employingthe above carboxylic acid and using carbonyldiimidazole in place ofoxalyl chloride and omitting the dimethylformamide. Quenching thereaction by addition of water followed by flash chromatography, elutingwith 5:2:2.5:0.5 methylene chloride-ethyl acetate-hexane-ethanol,affords the title compound as a white solid, m.p. 149°-151° C.

Analysis for: C₂₄ H₂₀ N₂ O₄ S.0.6 C₄ H₈ O₂ : Calculated: C, 65.33; H,5.10; N, 5.77. Found: C, 65.03; H, 4.76; N, 6.13.

EXAMPLE 314-{4-[(1-Methyl-1H-benzimidazol-2-yl)methoxy]phenyl}-5-phenyl-2-oxazoleN-hydroxy-N-methyl propanamide, hydrate 0.5 ethyl acetate solvate

The title compound is prepared using the method of part C of Example 30and employing the acid from Example 7. Normal workup affords whitecrystals, m.p. 148°-152° C.

Analysis for: C₂₈ H₂₆ N₄ O₄.0.5 C₄ H₈ O₂.H₂ O: Calculated: C, 66.17; H,5.92; N, 10.28. Found: C, 65.91; H, 5.28; N, 11.10.

EXAMPLE 32 4-{4-[(benzothiazol-2-yl)methoxy]-phenyl}-5-phenyl-2-oxazoleN-hydroxy-N-methyl propanamide

The acid, 4-{4-[(benzothiazol-2-yl)methoxy]-phenyl}-5-phenyl-2-oxazoleN-hydroxy-N-methyl propanoic acid, is first prepared using the method ofExample 7 substituting 2-(chloromethyl)benzothiazole forN-methyl-2-(chloromethyl)benzimidazole. The title compound is preparedusing the method of part C of Example 30 and employing the previouslyprepared acid. Normal workup affords white crystals, m.p. 152°-155° C.

Analysis for: C₂₇ H₂₃ N₃ O₄ S: Calculated: C, 66.79; H, 4.77; N, 8.65.Found: C, 66.59; H, 4.68; N, 8.48.

EXAMPLE 331-{1-[4'-(Benzothiazol-2-ylmethoxy)biphenyl-4-yl]-ethyl}-1-hydroxy-urea

A. 4-Acetoxy-4'-hydroxy-1,1'-biphenyl

The title compound is prepared using the method of part B of Example 16substituting 4-acetoxy-4'-methoxy-1,1'-biphenyl forα-methyl-4'-(methoxy)[1,1'-biphenyl]-4-acetic acid, ethyl ester. Normalworkup affords a white solid, m.p. 204°-207° C.; MS (EI m/z): 212 (M)⁺,197 (b.p.,M--CH₃)⁺.

B. 4-(α-Hydroxyethyl)-4'-hydroxy-1,1'-biphenyl

A solution containing 4-acetoxy-4'-hydroxy-1,1'-biphenyl from part A(5.0 g, 23.6 mmol) in methanol (500 mL) and tetrahydrofuran (30 mL) istreated with sodium borohydride (0.9 g, 23.8 mmol) in portions over 30minutes at room temperature. After 2 hours, the reaction mixture isconcentrated under reduced pressure, diluted with water (400 mL),acidified with 2N HCl and extracted with ethyl acetate. The organiclayer is washed with water and brine, dried over MgSO₄ and concentratedto a solid residue. Crystallization of the solid from ethyl acetategives 4.7 g (92.9%) of the title compound, m.p. 159°-160° C.; MS (EIm/z): 214 (M)⁺ and 199 (b.p. M--CH₃)⁺.

C. 4-(α-Hydroxyethyl)-4'-(benzothiazol-2-ylmethoxy)-1,1'-biphenyl

The title compound is prepared using the method of Example 11B employingthe above phenol. Normal workup gives 1.3 g (86.7%) of crystallineproduct, m.p. 205°-206° C.

Analysis for: C₂₂ H₁₉ NO₂ S: Calculated: C, 73.10; H, 5.30; N, 3.88.Found: C, 73.29; H, 5.27; N, 3.85.

D.N,O-Bis(tert-butoxycarbonyl)-1-{1-[4-(benzothiazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxylamine

To a mixture containing4-(a-hydroxyethyl)-4'-(benzothiazol-2-ylmethoxy)-1,1'-biphenyl from PartC (4.0 g, 11.1 mmol), triphenylphosphine (5.0 g, 22.0 mmol) andN,O-bis(tert-butoxycarbonyl)hydroxylamine (5.13 g, 22.0 mmol) intetrahydrofuran (160 mL) is added a solution of diethyl azodicarboxylate(1.5 mL, 11.1 mmol) in tetrahydrofuran (80 mL) over 30 minutes. Thereaction mixture is stirred overnight, concentrated to a volume of 50 mLand upon cooling at -10° C., the product crystallizes to give 4.0 g ofcrude material. Purification of the solid by chromatography (30% ethylacetate in hexane) yields 3.1 g (48.4%) of the title compound, m.p.139°-143° C.; MS (EI m/z): 376M)⁺.

E.1-{1-[4-(Benzothiazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxylamine

A solution ofN,O-bis(tert-butoxycarbonyl)-1-{1-[4-(benzothiazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxylaminefrom Part D (0.11 g, 0.19 mmol) in trifluoroacetic acid (3 mL) isstirred at room temperature for 30 minutes. The solution is poured into0.5N NaOH (100 mL) and the product crystallizes from the solution togive 0.85 g of a crude solid. Crystallization of the solid from ethylacetate and hexane gives 0.050 g (69.5%) of white solid material, m.p.176°-180° C. (dec.); MS (EI m/z): 376(M)⁺ and 344 (b.p., M-NHOH)⁺.

F.1-{1-[4-(Benzothiazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxy-urea

A solution of1-{1-[4-(benzothiazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxylaminefrom Part E (0.7 g, 1.86 mmol) and trimethylsilylisocyanate (1.5 mL,11.08 mmol) in dioxane (100 mL) is stirred for 24 hours. The mixture ispoured into saturated NH₄ Cl and the product crystallizes to give 0.7 gof a crude solid. Purification of this material by chromatography (THF)and trituration from diethyl ether yields 0.35 g of the title compound,m.p. 190°-191° C.; MS(CI m/z): 420 (M+H)⁺.

EXAMPLE 34N-{1-[4'-(Benzothiazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide

A.O-Acetoxy-N-{1-[4'-(benzothiazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide

To a solution of the hydroxylamine from part E of Example 33 (0.75 g,1.99 mmol) and triethylamine (0.61 g, 6.0 mmol) in methylene chloride(180 mL) and tetrahydrofuran (5 mL) is added slowly acetyl chloride(0.43 g, 6.0 mmol). After 1 hour, the mixture is poured into 2N HCl (200mL) and extracted. The methylene chloride layer is washed with water,brine, dried over MgSO₄ and concentrated to give 0.53 g of a crudesolid. Purification of the solid by chromatography (1:1 ethylacetate:hexane) gives 0.37 g (40.2%) of white crystalline titlecompound, m.p. 168°-174° C.

Analysis for: C₂₂ H₂₄ N₂ O₄ S: Calculated: C, 67.81; H, 5.25; N, 6.08.Found: C, 67.63; H, 5.23; N, 6.04.

B.N-{1-[4'-(Benzothiazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide

To a solution ofO-acetoxy-N-{1-[4'-(benzothiazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxy-acetamide(0.30 g, 0.652 mmol) in isopropyl alcohol (70 mL) and THF (15 mL) isadded dropwise a solution of LiOH (0.14 g, 3.26 mmol) in water (3 mL).After 30 minutes, the reaction mixture is neutralized with 2N HCl andconcentrated under reduced pressure. To the residue is added ethylacetate and water and the mixture is extracted. The organic layer iswashed with water, brine, dried over MgSO₄ and concentrated to give 0.25g of a crude solid. Crystallization of the solid from ethyl acetateyields 0.21 g (77.0%) of title compound as a white crystalline material,m.p. 197°-199° C.

Analysis for: C₂₄ H₂₂ N₂ O₃ S: Calculated: C, 68.88; H, 5.30; N, 6.69.Found: C, 69.07; H, 5.30; N, 6.56.

EXAMPLE 351-{1-[4'-(Benzoxazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxy-urea

A. 4-(α-Hydroxyethyl)-4'-(benzoxazol-2-ylmethoxy)-1,1'-biphenyl

The title compound is prepared using the method of Example 11B employingthe phenol from part B of Example 33 and substituting2-(chloromethyl)benzoxazole for 2-(chloromethyl)benzothiazole. Normalworkup gives 8.0 g (70.8%) of title compound as a crystalline product,m.p. 166°-169° C.

Analysis for: C₂₂ H₁₉ NO₃ : Calculated: C, 76.50; H, 5.54; N, 4.06.Found: C, 76.88; H, 5.76; N, 4.06.

B.N,O-Bis(tert-butoxycarbonyl)-1-{1-[4-(benzoxazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxylamine

The title compound is prepared using the method of part D. of Example 33and employing the compound from Part A. Normal workup yields 3.1 g(53.2%) of the title compound, m.p. 127°-132° C.; MS (CI m/z): 561(M+H)⁺.

Analysis for: C₃₂ H₃₆ N₂ O₇ : Calculated: C, 68.56; H, 6.47; N, 5.00.Found: C, 68.95; H, 6.48; N, 4.72.

C.1-{1-[4-(Benzoxazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxylamine

The title compound is prepared using the method of part E. of Example 33and employing the compound from Part B. Normal workup gives 2.7 g(71.7%) of the title compound as a white solid; MS (EI m/z): 360 (M)⁺and 328 (b.p., M-NHOH)⁺.

Analysis for: C₂₂ H₂₀ N₂ O₃ Calculated: C, 73.32; H, 5.59; N, 7.77.

Found: C, 73.13; H, 5.59; N, 7.93.

D. 1-{1-[4-(Benzoxazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxy-urea

The title compound is prepared using the method of part F. of Example 33and employing the compound from Part C. Normal workup gives 0.7 g of thetitle compound as white crystals, m.p. 167°-168° C.(dec.); MS (CI M/Z):404 (M+H)⁺.

EXAMPLE 36N-{1-[4'-(Benzoxazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide

A.O-Acetoxy-N-{1-[4'-(benzoxazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide

The title compound is prepared using the method of part A. of Example 34using the hydroxylamine from part C of Example 35. Normal workup gives1.6 g (99.0%) of the title compound as a white solid, m.p. 98.0°-100.0°C.

Analysis for: C₂₆ H₂₄ N₂ O₅ : Calculated: C, 70.26; H, 5.44; N, 6.30.Found: C, 70.27; H, 5.52; N, 6.16.

B.N-{1-[4'-(Benzoxazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide

The title compound is prepared using the method of part B. of Example 34and employing the compound of Part A. Normal workup gives 1.0 g (71.4%)of the title compound as a white crystalline material, m.p. 171°-172° C.

Analysis for: C₂₄ H₂₂ N₂ O₄ : Calculated: C, 71.63; H, 5.51; N, 6.96.Found: C, 71.56; H, 5.55; N, 6.88.

EXAMPLE 37N-Hydroxy-N-{1-[4'-(1-methyl-1H-benzimidazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-acetamide

A.4-(α-Hydroxyethyl)-4'-(1-methyl-1H-benzimidazol-2-ylmethoxy)-1,1'-biphenyl

The title compound is prepared using the method of Example 11B employingthe phenol from part C of Example 33 and substituting2-(chloromethyl)-1-methylbenzimidazole for 2-(chloromethyl)benzthiazole.Normal workup gives 7.0 g (59.7%) of the title compound as a crystallineproduct, m.p. 216°-219° C.

Analysis for: C₂₃ H₂₂ N₂ O₂ : Calculated: C, 77.07; H, 6.19; N, 7.82.Found: C, 77.41; H, 6.19; N, 7.69.

B.N,O-Bis(tert-butoxycarbonyl)-1-{1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxylamine

The title compound is prepared using the method of part D. of Example 33and employing the compound from Part A. Normal workup gives 9.2 g(82.0%) of the title compound.

C.1-{1-[4-(1-Methyl-1H-benzimidazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxylamine.TFAsalt

The title compound is prepared using the method of part E. of ExampleWAY-33 and employing the compound from Part B. Normal workup gives 3.1 g(55.4%) of the title compound as a white solid, m.p. 185°-187° C.(dec.); MS (CI m/z): 374 (M+H-TFA)⁺.

D.O-Acetoxy-N-{1-[4'-(1-methyl-1H-benzimidazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide

The title compound is prepared using the method of part A. of Example 34and employing the compound from Part C. Normal workup gives 0.65 g(35.5%) of the title compound as a white solid, m.p. 163°-169° C.; MS(CI m/z): 458 (M+H)⁺.

E.N-Hydroxy-N-{1-[4'-(1-methyl-1H-benzimidazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-acetamide

The title compound is prepared using the method of part B. of Example 34employing the compound from Part D. Normal workup gives 0.3 g (55.6%) oftitle compound as a white crystalline material, m.p. 211°-213° C.(decomposed).

Analysis for: C₂₅ H₂₅ N₃ O₃ Calculated: C, 72.27; H, 6.07; N, 10.11.Found: C, 72.10; H, 6.11; N, 9.93.

EXAMPLE 381-{1-[4'-(2-Phenylthiazol-4-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxy-urea

A. 4-(α-Hydroxyethyl)-4'-(2-phenylthiazol-4-ylmethoxy)-1,1'-biphenyl

The title compound is prepared using the method of Example 11B employingthe phenol from part C of Example 33 and substituting4-chloromethyl-2-phenylthiazole for 2-(chloromethyl)benzthiazole. Normalworkup gives 9.8 g (77.2%) of the title compound as a crystallineproduct, m.p. 164°-165° C.

Analysis for: C₂₄ H₂₁ NO₂ S: Calculated: C, 74.39; H, 5.46; N, 3.61.Found: C, 74.11; H, 5.43; N, 3.53.

B.N,O-Bis(tert-butoxycarbonyl)-1-{1-[4-(2-phenylthiazol-4-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxylamine

The title compound is prepared using the method of part D. of Example 33and employing the compound from Part A. Normal workup gives 8.0 g(54.1%) of the title compound as white crystals, m.p. 128°-129° C.

Analysis for: C₃₄ H₃₈ N₂ O₆ S: Calculated: C, 67.75; H, 6.35; N, 4.65.Found: C, 67.66; H, 6.33; N, 4.68.

C.1-{1-[4-(2-Phenylthiazol-4-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxylamine

The title compound is prepared using the method of part E. of Example 33and employing the compound from Part B. Normal workup gives 3.2 g(43.0%) of the title compound as a white solid, MS (EI m/z): (M)⁺.

Analysis for: C₂₄ H₂₂ N₂ O₂ S: Calculated: C, 71.62; H, 5.51; N, 6.96.Found: C, 71.23; H, 5.62; N, 6.57.

D.1-{1-[4-(2-Phenylthiazol-4-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxy-urea

The title compound is prepared using the method of part F of Example 33and employing the compound from Part C. Normal workup gives 0.75 g(56.1%) of the title compound, m.p. 175°-176° C. (decomposed); MS((+)FAB m/z): 446 (M+H)⁺.

EXAMPLE 39N-{1-[4'-(2-Phenylthiazol-4-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide

A.O-Acetoxy-N-{1-[4'-(2-Phenylthiazol-4-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide

The title compound is prepared using the method of part A. of Example 34and employing the compound from Part C of Example 38. Normal workupgives 1.6 g (78.4%) of the title compound as a white solid, m.p. 95°-96°C.; MS (CI m/z): 487 (M+H)⁺.

Analysis for: C₂₈ H₂₆ N₂ O₄ S: Calculated: C, 69.12; H, 5.39; N, 5.76.Found: C, 68.88; H, 5.43; N, 5.57.

B.N-{1-[4'-(2-Phenylthiazol-4-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide

The title compound is prepared using the method of part B. of Example 34and employing the compound from Part A. Normal workup gives 1.1 g(78.0%) of the title compound as a white crystalline material, m.p.183°-184.5° C.; MS (CI m/z): 445 (M+H)⁺.

Analysis for: C₂₆ H₂₄ N₂ O₃ S: Calculated: C, 70.25; H, 5.44; N, 6.30.Found: C, 70.07; H, 5.52; N, 6.25.

EXAMPLE 401-{1-[4'-(Benzothiazol-2-ylmethoxy)-2-fluoro-(1,1'-biphenyl)-4-yl]-ethyl}-1-hydroxy-urea

A.1-[4'-(Benzothiazol-2-ylmethoxy)-2-fluoro-(1,1'-biphenyl)-4-yl]-ethanone

The methoxy compound from part B of Example 2 is first converted to thecorresponding hydroxy compound by refluxing in 48% HBr in acetic acid.The title compound is prepared using the method of part B of Example 11employing the previously synthesized hydroxy-ketone. Normal workupaffords a white solid, m.p. 170°-172° C.

Analysis for: C₂₂ H₁₆ NO₂ SF: Calculated: C, 70.01; H, 4.27; N, 3.71.Found: C, 69.47; H, 4.27; N, 3.88.

B.1-[4'-(Benzothiazol-2-ylmethoxy)-2-fluoro-(1,1'-biphenyl)-4-yl]-ethanol

The title compound is prepared using the method of part B. of Example 33but substituting LiAlH₄ for sodium borohydride and employing thecompound from Part A. Normal workup followed by flash chromatography(eluant:hexane-ethyl acetate 6:4) affords the title compound.

C.1-{1-[4'-(Benzothiazol-2-ylmethoxy)-2-fluoro-(1,1'-biphenyl)-4-yl]-ethyl}-1-hydroxylamine

The title compound is prepared using the method of parts D and E ofExample 33 employing the above alcohol. Normal workup gives a whitesolid.

D.1-{1-[4'-(Benzothiazol-2-ylmethoxy)-2-fluoro-(1,1'-biphenyl)-4-yl]-ethyl}-1-hydroxy-urea

The title compound is prepared using the method of part F of Example 33employing the above hydroxylamine. Normal workup gives a white solid,m.p. 185°-186° C.

Analysis for: C₂₃ H₂₀ N₃ O₃ SF: Calculated: C, 63.14; H, 4.61; N, 9.60.Found: C, 62.35; H, 4.55; N, 8.80.

EXAMPLE 41

The compounds 5- and 12-hydroxyeicosatetraenoic acid (5-HETE and12-HETE) and LTB₄ are early arachidonic acid oxidation products in thelipoxygenase cascade, which have been shown to mediate several aspectsof inflammatory and allergic response. This is especially true withrespect to 5,12-diHETE, which is also denoted as LTB₄ [seeFord-Hitchinson, J. Roy. Soc. Med., 74, 831 (1981)]. Compounds whichinhibit the PLA₂ -mediated release of arachidonic acid therebyeffectively prevent the oxidation of arachidonic acid to the variousleukotriene products via the lipoxygenase cascade. Accordingly, thespecificity of action of PLA₂ inhibitors can be determined by theactivity of test compounds in this assay, which measures the ability ofcompounds to inhibit the synthesis of LTB₄ by rat glycogen-elicitedpolymorphonuclear leukocytes (PMN) in the presence of exogenoussubstrate.

The assay is carried out as follows:

Rat polymorphonuclear leukocytes (PMNs) are obtained from female Wistarrats (150-200 g) which receive an injection of 6% glycogen (10 ml i.p.).Rats are sacrificed 18-24 hours post injection by CO₂ asphyxiation andthe elicited cells are harvested by peritoneal lavage usingphysiological saline (0.9% NaCl). The exudate is centrifuged at 400 xgfor 10 minutes. The supernatant fluid is discarded and the cell pelletis resuspended to a concentration of 2.0×10⁷ cells/mL in HBSS containingCa⁺⁺ and Mg⁺⁺ and 10 μM L-cysteine.

To 1 mL aliquots of cell suspension, test drugs or vehicle are added,then preincubated at 37° C. for 10 minutes. A23187 (1 μM), [³ H]-AA (3.0μCi/mL) and unlabeled AA (1 μM) are then added and the samples arefurther incubated for 10 minutes. The reaction is terminated bycentrifugation and pelleting cells. Supernatants are then analyzed byHPLC analysis on a 15 cm×4.6 mm ID supelcosil LC-18 (Supelco)(3M)column, using a two solvent system at a flow rate of 1.4 mL total flowas follows:

Solvent A: 70:30 17.4 mM H₃ PO₄ :CH₃ CN.

Solvent B. CH₃ CN.

Gradient: (system is equilibrated with Solvent A).

    ______________________________________                                        Time         Percent A Percent B                                              ______________________________________                                        0            100        0                                                     15.0         100        0                                                     20.0         65        35                                                     40.0         65        35                                                     42.0         10        90                                                     50.0         10        90                                                     50.1         100        0                                                     ______________________________________                                    

Percent solvent changes are accomplished in a linear fashion.

Injections: 140 μL of each supernatant is injected directly onto columnand ³ H arachidonic acid metabolites are monitored using an on-lineradioactivity detector (Ramona, Ind./US, Fairfield, N.J.).

Standards: 10⁴ -2.0×10⁴ dpm of eicosanoids of interest are injected in90 μL EtOH cocktail.

Co-chromatography with standard [³ H] leukotriene B₄ (LTB₄) in medium ofstimulated PMN exposed to drug is compared to that found in medium ofstimulated cells exposed to no drug, generating percent inhibition.

Results are expressed as percent inhibition at a given compound dose oras an IC₅₀ value.

Testing compounds of the invention in this assay gave the followingresults:

                  TABLE I                                                         ______________________________________                                        Compound of                                                                   Example No.       % Inhibition                                                ______________________________________                                        ketoprofen        -50*    (at 10 μM)                                       1                 95      (at 0.5 μM)                                      2                 91      (at 0.5 μM)                                      3                 87      (at 10 μM)                                                         38      (at 0.5 μM)                                      4                 8       (at 10 μM)                                       5                 96      (at 10 μM)                                       6                 95      (at 10 μM)                                                         81      (at 0.5 μM)                                        6A              94      (at 10 μM)                                                         63      (at 0.5 μM)                                      7                 85      (at 10 μM)                                       ______________________________________                                         *a negative value denotes potentiation of cyclooxygenase (PGE.sub.2           synthesis)                                                               

EXAMPLE 42

The procedure of Example 41 is also employed for the determination ofthe extent to which compounds of the invention inhibit the synthesis ofthe arachidonic acid cyclooxygenase oxidation product PGE₂.

In this assay, the procedure of Example 41 is carried out as described.However, in order to determine cyclooxygenase activity, the samples areco-chromatographed with authentic reference [³ H]-PGE₂.

The results are calculated as in Example 41 and presented below:

                  TABLE II                                                        ______________________________________                                        Compound of                                                                   Example No.       % Inhibition                                                ______________________________________                                        ketoprofen        87      (at 10 μM)                                       1                 -13*    (at 0.5 μM)                                      2                 -22*    (at 0.5 μM)                                      3                 8       (at 10 μM)                                                         -8*     (at 0.5 μM)                                      4                 -31*    (at 10 μM)                                       5                 -275*   (at 10 μM)                                       6                 -191*   (at 10 μM)                                                         -12*    (at 0.5 μM)                                        6A              -79*    (at 10 μM)                                                         -29*    (at 0.5 μM)                                      7                 -268*   (at 10 μM)                                       ______________________________________                                         *Negative values denote a potentiation of cyclooxygenase (PGE.sub.2           synthesis).                                                              

EXAMPLE 43

The compounds of the invention are tested in an in vitro isolatedphospholipase A₂ assay to determine the ability of the test compounds toinhibit the release of arachidonic acid from an arachidonicacid-containing substrate by the action of phospholipase A₂ enzyme fromhuman and non-human sources.

This assay is carried out as follows:

Into a 15 mL polypropylene tube are added the following:

    ______________________________________                                        Agent          Volume, μL                                                                            Final Conc.                                         ______________________________________                                        .sup.3 H-AA E. coli substrate.sup.1                                                          25         5       nmoles PL                                   CaCl.sub.2 (0.1 M).sup.2                                                                      5         5       mM                                          Tris-HCl (0.5 M) pH 7.5.sup.3                                                                20         100     mM                                          Water.sup.4    25                                                             Drug/vehicle.sup.5                                                                            1         50      μM                                       PLA.sub.2      25         Volume yielding 12%                                                           hydrolysis in 10 min.                                              100                                                            ______________________________________                                         *pre-incubate at room temperature 30 min prior to substrate addition.         .sup.1 Prepared by adding 2 mL deionized and distilled water to 2 mL          .sup.3 Harachidonate labeled E. coli (lower count), to which is added 1 m     of .sup.3 Harachidonate labeled E. coli (higher count) to yield a total o     5 m substrate (containing 1000 nmoles phospholipid).                          .sup.2 Stock 0.1 m CaCl.sub.2, required for enzyme activity.                  .sup.3 Stock 0.5 m TrismaBase. Stock 0.5 M TrismaHCl. Adjust pH to 7.5        (optimum for enzyme).                                                         .sup.4 Deionized and distilled water.                                         .sup.5 Stock 10 mM prepared in dimethyl sulfoxide. Make 1:2 dilution with     dimethyl sulfoxide and add 1 μ L to 100 μL assay tube.                  .sup.6 Two human PLA.sub.2 enzymes are used:                                  a) Semipurified human platelet acid extract PLA.sub.2 (in 10 mM sodium        acetate buffer, pH 4.5). Remove protein precipitate by centrifugation at      about 2200 rpm to 10 minutes.                                                 b) Purified human synovial fluid.                                        

Incubate the 100 μL reaction mixture for 10 minutes at 37° C. in ashaking water bath. The reaction is terminated by the addition of 2 mLtetrahydrofuran, followed by vortexing. NH₂ columns (100μg/mL-Analytichem International) are conditioned with 0.5 mLtetrahydrofuran followed by 0.5 mL tetrahydrofuran/water (2 mL:0.1 mL,v/v).

The sample is loaded onto the columns and slowly drawn through them. Thehydrolyzed arachidonic acid retained in the columns is eluted therefromwith 1 mL tetrahydrofuran/glacial acetic acid (2%). The arachidonic acidis transferred to scintillation vials and quantitated by β-countinganalysis. A "total counts" sample is prepared by pipetting 25 μL ³H-arachidonate E. coli directly into a scintillation vial to which isadded 1 mL tetrahydrofuran. 10 mL aquasol (scintillation cocktail) isadded to all samples.

Calculations: ##EQU1##

Activity of Standard Drugs:

    ______________________________________                                                      IC.sub.50                                                       (μM)         Human Platelet                                                                            Human                                             ______________________________________                                        Synovial        PLA.sub.2                                                     Drug            PLA.sub.2                                                     Arachidonic Acid                                                                               8.6        3.2                                               Monoalide       25.2        0.14                                              ______________________________________                                    

When tested in this assay, the compounds of the invention gave thefollowing results:

                  TABLE III                                                       ______________________________________                                        Compound of  % Inhibition at 10 μM                                         Example No.  HSF*                                                             ______________________________________                                        ketoprofen   -16.9**                                                          3            25.5                                                             4            15.1                                                             ______________________________________                                         *human synovial fluid                                                         **negative values denote a potentiation of HSF                           

EXAMPLE 44

The compounds of the invention are evaluated for their ability toinhibit the lipoxygenase and/or cyclooxygenase pathways of arachidonicacid metabolism in the in vivo murine zymosan peritonitis assay.

This assay is carried out as follows:

Male CD-1 mice (8 weeks old) are placed in plastic boxes in groups ofsix. Animals are injected with 1 mL i.p. of either 1% zymosan in pyrogenfree 0.9% saline or saline (unstimulated control). Compounds are dosedorally 1 hour prior to zymosan injection. Twenty minutes after zymosaninjection, the mice are asphyxiated by CO₂ inhalation and the peritonealcavity is lavaged with 2 mL ice cold Hanks Balanced Salt Solution (HBSS)without CaCl₂, MgSO₄.7H₂ O and MgCl₂.6H₂ O. Peritoneal lavage fluid fromeach mouse is removed by syringe and placed in 5 mL plastic test tubesput on ice and volume is noted. Preparation of samples for evaluation byELISA is as follows: Samples are centrifuged at 800 xg for 15 minutes; 1mL of the supernatant is added to 8 mL ice cold methanol and kept at-70° C. overnight to precipitate protein; and samples are thencentrifuged at 800 xg for 15 minutes, followed by a drying procedure ina Savant speed vac concentrator. The samples are reconstituted with 1 mLice cold ELISA buffer and stored at -70° C. until assayed. The assay foreicosanoids (LTC₄ and 6-keto-PGF₁α) is performed according toconventional ELISA procedures.

Compounds to be tested orally are suspended in 0.5% Tween 80. Compoundsto be tested intraperitoneally are suspended in 0.5% methylcellulose in0.9% saline.

The total metabolite level in lavage fluid/mouse is calculated and thesignificance is determined by a one-way analysis of variance with LSDcomparisons to control (p≦0.05). Drug effects are expressed as a percentchange from control values.

The activity of standard drugs in this assay is as follows:

    ______________________________________                                                   ED.sub.50 mg/kg p.o.                                               Compound     LTC.sub.4 6-keto-PGF.sub.1α /TxB.sub.2                     ______________________________________                                        BW755C       <10       22.0                                                   Phenidone    24.0      <30.0                                                  Indomethacin Not Active                                                                              0.126                                                  Ibuprofen    Not Active                                                                              7.0                                                    ______________________________________                                    

When tested in this assay a compound of the invention and theanti-inflammatory compound etodolac gave the following results:

                  TABLE IV                                                        ______________________________________                                        Compound of                                                                              Dose         % Inhibition                                          Example No.                                                                              mg/kg        LTC.sub.4                                                                             6-keto-PGF                                    ______________________________________                                        5          10 (i.p.)*   86      -27**                                         ______________________________________                                         *intraperitoneally administered                                               **negative values denote potentiation                                    

The results show that the compound of the invention exerts a potentinhibitory effect on the lipoxygenase pathway but not on thecyclooxygenase pathway.

EXAMPLE 45

The compounds of the invention are further tested in the reverse passiveArthus pleurisy assay to evaluate their effectiveness in inflammatorymediator release and/or the fluid and cellular phases of an inflammatoryresponse.

This assay is carried out as follows:

A reverse passive Arthus reaction is induced in the pleural cavity ofmale Lewis rats (150-200 g; fasted overnight prior to use) by theintravenous administration of bovine serum albumin (BSA; 4 mg/0.2 ml)followed 30 minutes later by the injection of rabbit anti-BSA (1 mg/0.2ml; lyophilized IgG fraction; Organon Teknika, West Chester, Pa.) intothe right pleural space under halothane anesthesia. Drugs or vehicle(0.5% Tween-80) control are administered orally in a volume of 1 ml/100g body weight at 1 hour prior to the anti-BSA. Animals are sacrificed ateither the time of peak eicosanoid production (i.e. 5 minutes afteranti-BSA for immunoreactive TxB₂ 10 minutes for immunoreactive LTB₄, 20minutes for immunoreactive LTC₄) or at the time of peak neutrophilinfiltration (4 hours after anti-BSA) by CO₂ inhalation. The pleuralcavity is then exposed, the fluid exudate removed by gentle vacuumaspiration and the volume of exudate is recorded. For the determinationof cellular infiltration, the pleural cavity is rinsed with 3 ml of 0.1%EDTA in sterile saline, and the recovered wash is pooled with theexudate. Cell number is determined on a model ZBI Coulter counter. Fordetermination of eicosanoid production, undiluted pleural exudate ismicrofuged and the supernatant is extracted with ethanol (8-10 timesvolume). Extracts are either stored at -20° C., or are evaporated todryness under a stream of N₂ and reconstituted in radioimmunoassay (RIA)buffer.

Eicosanoids are quantitated by RIA according to the procedure specifiedby the RIA kit manufacturer (Advanced Magnetics, Cambridge, Mass.).Briefly, 100 μl of ³ H-labeled eicosanoid and 100 μl of specificantibody are sequentially added to 100 μl of extracted pleural exudatein BGG -phosphate buffer which contains 0.01M phosphate, 0.1% bovinegamma globulin and 0.1% sodium azide at pH 7.0. Antibody-boundeicosanoid is separated from unbound eicosanoid by the addition of 750μl of dextran (0.4%)-coated charcoal (0.4% Norit A) containing 0.1%sodium azide. The mixture is centrifuged at 2000 RPM at 5° C. for 15minutes to pellet the charcoal and adsorbed unbound eicosanoid.Antibody-bound labeled eicosanoid is quantitated by counting in a liquidscintillation counter, and is correlated to concentration by a standardcurve.

Inflammatory cells are expressed as 10⁶ cells/ml, pleural exudate isexpressed as ml of fluid, and the amount of eicosanoids in the pleuralcavity is expressed as ng/ml of exudate. Mean±S.E.M. is determined foreach group. Percent inhibition (% I) of cell number, exudate volume andeicosanoid production is calculated for vehicle-treated control groups,and the responses in drug-treated rats are then expressed as the mean %I of the control. The ED₃₀ or ED₅₀ with 95% confidence limits iscalculated by the method of Litchfield and Wilcoxon, J. Pharmac. Exp.Ther., 96, 99-113 (1949).

The activity of standard drugs in this assay is as follows:

    __________________________________________________________________________    A. Inflammatory Mediator Release:                                             Antiinflammatory     ED.sub.50 (mg/kg p.o.)                                   Drug     Class       TxB.sub.2 LTB.sub.4                                      __________________________________________________________________________    Indomethacin                                                                           NSAID; CO inhibitor                                                                       0.16      12% Inh (4 mg/kg)                              Naproxen             0.24      0% Inh (4 mg/kg)                               Diclofenac           6.0        0% Inh (10 mg/kg)                             Ketoprofen           0.18      35% Inh (10 mg/kg)                             Wy-50,259-A                                                                            LO Inhibitor                                                                              0% Inh (75 mg/kg)                                        BW540C   Mixed CO/LO Inhibitor                                                                     19        30                                             BW755C               18        23                                             Phenidone            69        10                                             __________________________________________________________________________

    ______________________________________                                        B. Pleural Inflammation:                                                      Anti-            ED.sub.30 (mg/kg p.o.)                                       inflammatory         Fluid     Cellular                                       Drug     Class       Exudation Influx                                         ______________________________________                                        Indomethacin                                                                           NSAID;      2.5       19% Inh (8 mg/kg)                                       CO inhibitor                                                         Naproxen             3.9       29% Inh (8 mg/kg)                              Piroxicam            1.0       3.0                                            BW755C   Mixed CO/LO 14        28                                                      inhibitor                                                            Phenidone            21        23                                             Dexa-    Steroid     0.05      0.13                                           methasone                                                                     ______________________________________                                    

When tested in this assay, the compounds of the invention gave thefollowing results:

                  TABLE VI                                                        ______________________________________                                        Compound of   % Inhibition of                                                                            ED.sub.50                                          Example No.   LTB.sub.4 Synthesis*                                                                       (mg/kg)                                            ______________________________________                                         2            34                                                               9                         0.8                                                10            65                                                              15            12% at 10 mg/kg                                                 16            46                                                              17            37                                                              18            32                                                              20            19                                                              21             8                                                              22            37                                                              24            56                                                              26             7                                                              30            21                                                              33             2                                                              ______________________________________                                         *At 25 mg/kg p.o. unless otherwise specified, drugs administered 3 hours      before challenge.                                                        

The results show that the compounds tested have an effect in inhibitingthe release of inflammatory mediators and in inhibiting the fluid andcellular phases of the inflammatory response.

EXAMPLE 46

The assay of this Example measures the ability of the compounds testedto inhibit 5-lipoxygenase in human whole blood.

This assay is carried out as follows:

Blood is obtained in 50-100 ml quantities from male donors. White bloodcell counts and differentials are made. Two ml of blood are placed in a15 ml polypropylene test tube. Compounds are solubilized indimethylsulfoxide and diluted 1:10 in 10% bovine serum albumin inphosphate buffered saline, pH 7.4 resulting in a final dimethylsulfoxideconcentration of 0.1% in the blood. Then, compounds are added to theblood in a shaking water bath at 37° C. for 10 minutes prior to theaddition of 30 μM calcium ionophore (A23187; Sigma). After ionophoreadministration, whole blood samples are mixed and incubated for 20minutes at 37° C. in a shaking water bath. Incubation is terminated byplacing samples in an ice bath and immediately adding ethyleneglycol-bis-(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (10 mM).Samples are mixed and centrifuged at 1200×g for 15 minutes at 4° C.Preparation of samples for evaluation by RIA or ELISA is carried out bythe following protocol. Plasma is removed from sample tubes, placed in15 ml polypropylene test tubes containing 8 ml methanol, and thenvortexed to precipitate protein. Samples are stored at -70° C.overnight. The next day, samples are centrifuged at 200×g for 15 minutesat 4° C. to pellet the precipitate. Samples are dried in a Savant speedvac concentrator, reconstituted to original volume with ice cold RIA orELISA buffer, and stored at -70° C. until assayed. The assay foreicosanoids (LTB₄, TxB₂, and PGE₂) is performed as described by themanufacturer of the [³ H]-RIA kit or ELISA kit (LTB₄ -Amersham, TxB₂ andPGE₂ -Caymen Chemical).

The total eicosanoid level in 2 ml of blood is calculated and reportedas ng/10⁶ neutrophils. Significance is determined by a one-way analysisof variance with least significant difference (LSD) comparisons tocontrol (p≦0.05) and IC₅₀ 's (μM) are determined by regression analysis(Finney, 1978). Drug effects are expressed as percent change fromcontrol values.

Compounds tested in vitro are solubilized in dimethylsulfoxide anddiluted 1:10 in 10% bovine serum albumin in phosphate buffer salineresulting in a final dimethylsulfoxide concentration of 0.1% in theblood.

The results for compounds of the invention tested in this assay arepresented in Table VII.

                  TABLE VII                                                       ______________________________________                                        Compound of     % Inhibition                                                                             IC.sub.50                                          Example No.     of LTB.sub.4 *                                                                           (μM)                                            ______________________________________                                         2               5                                                             5              11                                                             8              94         0.53                                               14               5                                                            15              77                                                            16              72         8.3                                                18              97         0.5                                                19              83                                                            20              93                                                            21              85         7.8                                                22              74         9.0                                                23              32         11.9                                               26              86         1.3                                                27              69         1.3                                                28               66**      2.3                                                29               74**      0.7                                                30               96**      0.98                                               33               10**                                                         34               36**                                                         35               51**                                                         36               77**                                                         37               61**                                                         38               46**                                                         39               43**                                                         40               47**                                                         ______________________________________                                         *At 25 μM unless otherwise specified.                                      **At 10 μM.                                                           

EXAMPLE 47

The LTD₄ antagonist activity of the compounds of the invention isassessed in the in vitro isolated guinea pig trachea assay.

This assay is carried out as follows:

Male Hartley guinea pigs (350-400 g) are euthanized by a blow to thehead, the neck is opened and the trachea removed. The trachea ismaintained in aerated physiological salt solution, cleared of connectivetissue and fat and cut into rings approximately 2 mm in width (usuallycontaining two cartilaginous segments per ring). Two pieces of silksuture are then passed through the lumen of the tracheal ring and aretied around the cartilage, one on each side of the trachealis muscle.The tracheal ring is suspended between a glass hook and a forcedisplacement transducer in a 10 ml organ bath for measurement ofisometric tension. Tissues are maintained at 37° C. in aerated (95% CO₂/5% CO₂) physiological salt solution of the following composition: NaCl(100 mM), KH₂ PO₄ (1.18 mM), KCl (4.74 mM), CaCl₂ (2.5 mM), MgSO₄ •7H₂ O(1.19 mM), NaHCO₃ (25 mM), dextrose (11.1 mM) and indomethacin (1 μM).The tracheal rings are maintained at 2 g resting tension andequilibrated for 45 minutes (with frequent washing and readjustment ofresting tension).

The tracheal rings are first contracted by the addition of carbachol(3×10⁻⁶ M), to determine tissue responsiveness and establish a referencecontraction. On attainment of a stable level of contraction(approximately 30 minutes), the tissues are washed several times untilbaseline tension has been restored and the re-equilibrated for 30minutes. The tissues are then incubated for 45 minutes with a testantagonist (either 1×10⁻⁶ M or 1×10⁻⁵ M) or 10 μl of an appropriatesolvent control (control, non-treated). One tissue in each group servesas the control. Twenty minutes prior to the construction of the LTD₄cumulative concentration-response curve, L-cysteine (1×10⁻² M final bathconcentration) is added to inhibit bioconversion of LTD₄ to LTE₄. Onlyone LTD₄ concentration-response curve is constructed in each tissue.

All responses to LTD₄ in an individual tissue are measured as apercentage of the reference contraction of that tissue to carbachol.LTD₄ antagonist activity is determined by comparison of theconcentration response curves of LTD₄ in the presence and absence ofantagonist. Assessment of the relative rightward shift of the antagonisttreated curve relative to the solvent (control) treated tissue iscalculated as a concentration ratio (Eq. A) and used in subsequentcalculations to derive an antagonist pK_(B) value (Eqs. B and C). In theevent that the maximum response to LTD₄ is depressed, the EC₅₀ for thatparticular curve is determined, an "apparent" pK_(B) reported, and thecompound reported as "not-competitive." ##EQU2##

If a compound is found to be active and/or depress the maximal responseto LTD₄, then a range of concentrations of the test compound should beused generating multiple concentration ratios which would then be usedto perform a Schild analysis, and determination of a pA₂ value whereappropriate.

The activity of reference leukotriene antagonists in this assay is asfollows:

    ______________________________________                                        Compound      pK.sub.B                                                        ______________________________________                                        Ly-171,883    7.44 ± 0.12                                                  Wy-48,252     6.90 ± 0.23                                                  ______________________________________                                    

When tested in this assay, a compound of the invention gave thefollowing results:

                  TABLE VIII                                                      ______________________________________                                        Compound of                                                                   Example No.   pK.sub.B                                                                             Concentration Ratio (M)                                  ______________________________________                                         2             6.2   1 × 10.sup.-5                                       5             6.5   1 × 10.sup.-5                                      14            <5.1   1 × 10.sup.-5                                      15            <5.0   1 × 10.sup.-5                                      17            <5.5   1 × 10.sup.-5                                      18            <5.1   1 × 10.sup.-5                                      20            <5.2   1 × 10.sup.-5                                      21            <5.0   1 × 10.sup.-5                                      22             5.3   1 × 10.sup.-5                                      24             6.0   1 × 10.sup.-5                                      25            <5.1   1 × 10.sup.-5                                      26            <5.0   1 × 10.sup.-5                                      28            <5.4   1 × 10.sup.-5                                      29             6.2   1 × 10.sup.-5                                      33            <5.0   1 × 10.sup.-5                                      34            <5.0   1 × 10.sup.-5                                      35            <5.3   1 × 10.sup.-5                                      37            <5.5   1 × 10.sup.-5                                      ______________________________________                                    

The above results demonstrate that the compounds tested exhibitleukotriene antagonist activity as measured in the in vitro isolatedguinea pig trachea assay.

EXAMPLE 48

The ability of the compounds of the invention to inhibit thebiosynthesis of LTB₄ by isolated human neutrophils is evaluated in thefollowing assay, which is carried out in this manner:

Isolation of Human Polymorphonuclear Neutrophils

A leukocyte enriched blood sample obtained from a healthy male donor isprocured by leukophoresis using a Haemonetics model 30+ blood processor(Biological Specialties, Inc., Lansdale, Pa.). The top "platelet-rich"layer is removed after a low speed spin (35×g, 15 min, 25° C.) of thesample. The remaining cell suspension is centrifuged (400×g, 10 min, 25°C.) to sediment the remaining cells. The supernatant is discarded andthe cell pellet resuspended in 120 ml HBSS (without Ca⁺⁺ /Mg++). Thecell suspension is subjected to ficoll-hypaque sedimentation (Histopaque1077, 400×g, 30 min, 25° C.). Contaminating erythrocytes are lysed byhypotonic shock (1 min). The cells are then washed once with 40 ml ofHBSS and resuspended with HBSS (without Ca⁺⁺ /Mg⁺⁺) to a concentrationof 2.5×10⁷ cells/ml for further use. Greater than 95% purity is obtainedas assessed by microscopic examination.

LTB₄ Biosynthesis in Human PMN

One ml of human PMN (2.5×10⁷ cells/ml) is incubated with vehicle ordrugs (10 μl) for 10 min at 30° C. After preincubation, an equal volumeof HBSS (1 ml) containing 2.4 mM CaCl₂, 6 μM calcium ionophore A23187and 50 μCi [³ H]-acetate is then incubated at 30° C. for 15 minutes. Analiquot (100 μl) of the reaction mixture is taken out and mixed with 900μl of 15% ethanol. LTB₄ is extracted by using solid phase extraction onreverse phase C₁₈ columns to remove excess [³ H]-acetate and PAF. TheC₁₈ column is prewashed once with 2 ml of ethanol and water. The samplealiquot is acidified with 0.1N HCl to pH3 before applying to the column.The column is then washed with 2 ml of water followed by 2 ml of 15%ethanol and 2 ml of petroleum ether to remove excess labeled acetate.The sample is eluted with 2 ml of ethyl acetate. The collected samplesare dried with nitrogen and resuspended in 0.5 ml RIA buffer. Thequantity of LTB₄ in the sample is obtained from RIA determination.

Data presented are the means +/- s.d. of the values relative to controlA23187 stimulated cells for each experiment assayed in triplicate.Percent inhibition when used is calculated as: ##EQU3## Dose responseanalysis is performed by non-linear regression analysis for curvefitting and IC₅₀ determination.

The results for compounds of the invention tested in this assay arepresented in Table IX.

                  TABLE IX                                                        ______________________________________                                        Compound of   % Inhibition of                                                 Example No.   LTB.sub.4 Synthesis*                                            ______________________________________                                        12            Inactive                                                        13            98.9                                                            21            91.2                                                            23            99.0                                                            A-64,077      75.8                                                            ______________________________________                                         *At 2.5 μM.                                                           

What is claimed is:
 1. A compound having the formula

    A(CH.sub.2).sub.n O--B

wherein A is a group having the formula ##STR34## wherein Xis--N--;Z is--S-- or --O--; R¹ is hydrogen, lower alkyl or phenyl; R² is hydrogen orlower alkyl; or R¹ and R² taken together form a benzene ring, with theproviso that when B is a substituted diphenyloxazole, A is also phenyl,unsubstituted or mono or adjacent dilower alkyl substituted, ornaphthyl; n is 1-2; B is ##STR35## wherein Y is OR⁵ or N(OH)R⁸ ;R⁴ andR⁵ are each, independently , hydrogen or lower alkyl; R⁶ is hydrogen,halo or nitro; R⁷ is ##STR36## R⁸ is lower alkyl; m is 0-3;and thepharmacologically acceptable salts thereof.
 2. The compound of claim 1,having the name 4-[4-[2-naphthalenyl-methoxy]phenyl]-5-phenyl-2-oxazolepropanoic acid.
 3. The compound of claim 1, having the name4-[4-[2-naphthalenyl-methoxy]phenyl]-5-phenyl-2-oxazole propanoic acidmethylester.
 4. The compound of claim 1, having the name4-[4-[(1-methyl-1H-benzimidazol-2-yl)methoxy]phenyl]-5-phenyl-2-oxazolepropanoic acid.
 5. The compound of claim 1, having the name4'-(2benzothiazolylmethoxy)-4-diphenylacetic acid, ethyl ester.
 6. Thecompound of claim 1, having the name4'-(benzothiazolylmethoxyl)-4-diphenylacetic acid.
 7. The compound ofclaim 1, having the name4'-(benzothiazolylmethoxy)-4-diphenyl-N-hydroxy-N-methyl-acetamide. 8.The compound of claim 1, having the nameN-hydroxy-4'-(2-benzothiazolylmethoxy)-[1,1'-biphenyl]-4-acetamide. 9.The compound of claim 1, having the nameN-hydroxy-N-isopropyl-4'-(2-benzothiazolylmethoxy)-[1,1'-biphenyl]-4-acetamide.10. The compound of claim 1, having the nameN-hydroxy-N,α-dimethyl-4'(2-benzothiazolylmethoxy)-[1,1'-biphenyl]-4-acetamide.11. The compound of claim 1, having the nameN-hydroxy-N,α-dimethyl-4'-(2-benzothiazolylmethoxy)-[1,1'-biphenyl]-4-acetamide.12. The compound of claim 1, having the nameN-hydroxy-N-methyl-4'-[(2-phenylthiazol-4yl)methoxy]-[1,1'-biphenyl]-4-acetamide.13. The compound of claim 1, having the nameN-hydroxy-N-methyl-4'-[(2-phenylthiazol-4-yl)methoxy]-[1,1'-biphenyl]-4-acetamide.14. The compound of claim 1, having the nameN-hydroxy-N-isopropyl-4'-[(2-phenylthiazol-4-yl)methoxy]-[1,1'-biphenyl]-4-acetamide.15. The compound of claim 1, having the nameN-hydroxy-N,α-dimethyl-4'-[(2-phenylthiazol-4-yl)methoxy]-[1,1'-biphenyl]-4-acetamide.16. The compound of claim 1, having the nameN-hydroxy-N,α-dimethyl-4'-[(2-phenylthiazol-4-yl)methoxy]-[1,1'-biphenyl]-4-acetamide.17. The compound of claim 1, having the nameN-hydroxy-N-methyl-2-phenyl-α-[4'-[(2-phenylthiazol-4-yl)methoxy]-[1,1'-biphenyl]-4-yl]-thiazolepropanamide.18. The compound of claim 1, having the name4'-(benzothiazolylmethoxy)-2-fluoro-N-hydroxy-N-methyl-[1,1'-biphenyl]-4-acetamide.19. The compound of claim 1, having the name2-fluoro-N-hydroxy-N-methyl-4'-[2-phenyl-4-thiazolyl)methoxy]-[1,1'-bipheynl]-4-acetamide.20. The compound of claim 1, having the name2-{3-[4-(benzothiazol-2-ylmethoxy)-benzoyl]-phenyl}-N-hydroxy-N-methyl-4-acetamide.21. The compound of claim 1, having the name4-{4-[(1-methyl-1H-benzimidazol-2-yl)methoxy]phenyl}-5-phenyl-2-oxazoleN-hydroxy-N-methyl propanamide.
 22. The compound of claim 1, having thename 4-{4-[(benzothiazol-2-yl)methoxy]-phenyl}-5-phenyl-2-oxazoleN-hydroxy-N-methyl propanamide.
 23. The compound of claim 1, having thename1-{1-[4'-(benzothiazol-2-ylmethoxy)biphenyl-4-yl]-ethyl}-1-hydroxy-urea.24. The compound of claim 1, having the nameN-{1-[4'-(benzothiazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide.25. The compound of claim 1, having the name1-{1-[4'-(benzoxazol-2-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxy-urea.26. The compound of claim 1, having the nameN-{1-[4'-(benzoxazol-2-ylmethoxy)-biphenyl-4-yl]ethyl}-N-hydroxy-acetamide27. The compound of claim 1, having the name1-{1-[4'-(2-phenylthiazol-4-ylmethoxy)-biphenyl-4-yl]-ethyl}-1-hydroxy-urea.28. The compound of claim 1, having the nameN-{1-[4'-(2-phenylthiazol-4-ylmethoxy)-biphenyl-4-yl]-ethyl}-N-hydroxy-acetamide.29. The compound of claim 1, having the name1-{1-[4'-(benzothiazol-2-ylmethoxy)-2-fluoro-(1,1'-biphenyl)-4-yl]-ethyl}-1-hydroxy-urea.